ftsI

UniProt ID: P0AD68
Organism: Escherichia coli (strain K12)
Review Status: COMPLETE
Aliases:
PBP3 PbpB b0084 JW0082
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Gene Description

FtsI (also known as PBP3/PbpB) is an essential peptidoglycan D,D-transpeptidase required for cell division in E. coli. It is a Class B high-molecular-mass penicillin-binding protein that catalyzes cross-linking of peptidoglycan at the division septum. FtsI is a monofunctional transpeptidase - unlike Class A PBPs, it lacks glycosyltransferase activity. FtsI forms a subcomplex with FtsW (a SEDS protein that provides glycosyltransferase activity) and interacts with multiple divisome proteins including FtsQ, FtsL, FtsN, and PBP1b. FtsI localizes to the division septum during later stages of cell growth and throughout septation. Inhibition by beta-lactam antibiotics like penicillin blocks cell division causing filamentation.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: FtsI is an integral membrane protein with a single transmembrane helix that anchors it to the plasma membrane. The bulk of the protein protrudes into the periplasmic space [PMID:2677607]. UniProt confirms "Cell inner membrane; Single-pass membrane protein; Periplasmic side."
Reason: Well-supported by phylogenetic inference (IBA) and consistent with the experimentally determined topology of FtsI. The protein contains an N-terminal transmembrane anchor and the periplasmic catalytic domain [PMID:2677607, PMID:9614966].
Supporting Evidence:
file:ECOLI/ftsI/ftsI-deep-research-falcon.md
See deep research file for comprehensive analysis
GO:0008658 penicillin binding
IBA
GO_REF:0000033 		ACCEPT
Summary: FtsI (PBP3) is one of the major penicillin-binding proteins in E. coli. Spratt 1975 [PMID:1103132] showed that beta-lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3.
Reason: Core function of FtsI. Penicillin binding is essential for the mechanism of action of beta-lactam antibiotics against FtsI. Experimentally demonstrated by IDA [PMID:1103132] and confirmed by IBA phylogenetic inference.
Supporting Evidence:
PMID:1103132
beta-Lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3 (molecular weight 60,000)
GO:0071555 cell wall organization
IBA
GO_REF:0000033 		ACCEPT
Summary: FtsI participates in peptidoglycan synthesis at the division septum, contributing to cell wall organization during cell division. Botta and Park [PMID:6450748] showed PBP3 activity is required for septal murein synthesis.
Reason: Appropriate biological process annotation. FtsI functions in cell wall synthesis specifically during septation. The IBA inference is supported by extensive experimental evidence.
Supporting Evidence:
PMID:6450748
These results support the hypothesis that PBP-3 activity is exclusively required for septal murein synthesis
GO:0000917 division septum assembly
IEA
GO_REF:0000043 		ACCEPT
Summary: FtsI is essential for division septum assembly. It localizes to the septum and provides the transpeptidase activity necessary for cross-linking peptidoglycan during septation [PMID:9603865, PMID:28419603].
Reason: Core biological process for FtsI. The IEA annotation based on UniProt keywords is appropriate and supported by extensive experimental evidence from multiple publications.
Supporting Evidence:
PMID:9603865
The localization of FtsI (PBP3), a penicillin-binding protein specifically required for cell division in Escherichia coli, was investigated by immunofluorescence microscopy and found to localize to the septum
PMID:28419603
Cell division in Escherichia coli is mediated by a large protein complex called the divisome
GO:0004180 carboxypeptidase activity
IEA
GO_REF:0000043 		ACCEPT
Summary: FtsI has D,D-transpeptidase activity classified under EC 3.4.16.4 (serine-type D-Ala-D-Ala carboxypeptidase). This activity involves cleavage of the D-Ala-D-Ala bond and transpeptidation.
Reason: Appropriate general MF term. FtsI catalyzes the cleavage of the terminal D-alanine from peptidoglycan precursors during transpeptidation, which is a type of carboxypeptidase activity. More specific term GO:0009002 is also annotated.
Supporting Evidence:
PMID:3531167
Activity of penicillin-binding protein 3 from Escherichia coli
GO:0005886 plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Duplicate annotation for plasma membrane localization via combined IEA methods. FtsI is a membrane-anchored protein.
Reason: Correct localization. Duplicates with different evidence codes are acceptable as they provide independent support.
GO:0006508 proteolysis
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: FtsI has peptidase activity (D,D-transpeptidase) that involves cleavage of peptide bonds in peptidoglycan precursors during cell wall synthesis.
Reason: While technically accurate (FtsI cleaves D-Ala-D-Ala bonds), this is a very broad term. The more specific biological process is peptidoglycan biosynthesis, not general proteolysis. Keep as non-core.
GO:0008233 peptidase activity
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: FtsI has D,D-transpeptidase activity that involves peptide bond cleavage.
Reason: Accurate but very general. The more specific term GO:0009002 (serine-type D-Ala-D-Ala carboxypeptidase activity) is more informative. Keep as non-core supporting annotation.
GO:0008360 regulation of cell shape
IEA
GO_REF:0000043 		MARK AS OVER ANNOTATED
Summary: FtsI is involved in septation-specific peptidoglycan synthesis. While cell division affects cell shape, FtsI is not primarily a shape-regulating protein like PBP2 (which determines rod shape). FtsI specifically functions in division, not elongation.
Reason: Spratt 1975 [PMID:1103132] showed distinct PBPs for division (PBP3/FtsI), elongation (PBP1), and shape (PBP2). FtsI loss causes filamentation but does not alter cell shape in the way PBP2 mutations do. This annotation conflates division with shape regulation.
Supporting Evidence:
PMID:1103132
Cell shape: beta-Lactams that specifically result in the production of ovoid cells bind to penicillin binding protein 2... Cell division: beta-Lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3
GO:0008658 penicillin binding
IEA
GO_REF:0000120 		ACCEPT
Summary: Duplicate annotation for penicillin binding via combined IEA methods.
Reason: Core molecular function. Duplicates with different evidence sources are acceptable.
GO:0008955 peptidoglycan glycosyltransferase activity
IEA
GO_REF:0000002 		REMOVE
Summary: INCORRECT ANNOTATION. FtsI is a Class B PBP that lacks glycosyltransferase activity. UniProt explicitly states: "Was originally thought to be a bifunctional enzyme with transglycosylase and transpeptidase activities" (CAUTION). The SEDS protein FtsW provides the glycosyltransferase activity in the FtsI-FtsW complex [PMID:27525505].
Reason: This is a well-documented error. Meeske et al. 2016 [PMID:27525505] clearly state that Class B PBPs "have TP domains but lack PGT activity." The glycosyltransferase activity is provided by SEDS proteins (FtsW for division, RodA for elongation), not by Class B PBPs like FtsI. The InterPro mapping that generated this IEA annotation is incorrect for FtsI.
Supporting Evidence:
PMID:27525505
Under these conditions, cross-linking of adjacent glycan strands is likely carried out by the essential Class B PBPs (for simplicity, bPBPs), which have TP domains but lack PGT activity
GO:0009002 serine-type D-Ala-D-Ala carboxypeptidase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: FtsI catalyzes the transpeptidation reaction that cross-links peptidoglycan strands. The EC number 3.4.16.4 describes this activity: "Preferential cleavage: (Ac)2-L-Lys-D-Ala-|-D-Ala. Also transpeptidation of peptidyl-alanyl moieties."
Reason: Core molecular function of FtsI. This is the primary enzymatic activity that FtsI performs - a serine-type D,D-transpeptidase that cleaves D-Ala-D-Ala bonds and catalyzes transpeptidation to cross-link peptidoglycan.
Supporting Evidence:
PMID:3531167
Activity of penicillin-binding protein 3 from Escherichia coli
PMID:7030331
Peptidoglycan synthetic enzyme activities of highly purified penicillin-binding protein 3
GO:0009252 peptidoglycan biosynthetic process
IEA
GO_REF:0000120 		ACCEPT
Summary: FtsI is directly involved in peptidoglycan biosynthesis, specifically the cross-linking step at the division septum [PMID:6450748].
Reason: Core biological process. FtsI catalyzes the transpeptidation reaction that cross-links peptidoglycan strands during septal cell wall synthesis. This is UniProt pathway annotation (UPA00219).
Supporting Evidence:
PMID:6450748
Evidence for involvement of penicillin-binding protein 3 in murein synthesis during septation
GO:0016787 hydrolase activity
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: FtsI has hydrolase activity as part of its transpeptidase mechanism (cleavage of D-Ala-D-Ala bonds).
Reason: Very general term. More specific terms like GO:0009002 are more informative. Keep as non-core ancestor term.
GO:0043093 FtsZ-dependent cytokinesis
IEA
GO_REF:0000104 		ACCEPT
Summary: FtsI functions in FtsZ-dependent cell division. FtsI localization to the septum requires prior localization of FtsZ [PMID:9603865].
Reason: Appropriate biological process. FtsI is part of the divisome that assembles on the FtsZ ring scaffold. Localization is dependent on FtsZ [PMID:9603865].
Supporting Evidence:
PMID:9603865
The localization of FtsI was not observed in ftsZ or ftsA mutants, indicating that it was dependent on the prior localization of these proteins
GO:0051301 cell division
IEA
GO_REF:0000120 		ACCEPT
Summary: FtsI is essential for cell division. Inhibition causes filamentation and cell death [PMID:1103132].
Reason: Core biological process. FtsI is required for septation and cell division. Well-supported by experimental evidence.
Supporting Evidence:
PMID:1103132
Cell division: beta-Lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3
GO:0071555 cell wall organization
IEA
GO_REF:0000043 		ACCEPT
Summary: Duplicate annotation for cell wall organization via UniProt keyword mapping.
Reason: Appropriate biological process. Duplicates acceptable with different evidence.
GO:0005515 protein binding
IPI
PMID:15774864
Interaction network among Escherichia coli membrane proteins... 		MODIFY
Summary: FtsI interacts with FtsQ (P06136) as shown by bacterial two-hybrid analysis [PMID:15774864]. FtsQ is an essential divisome protein.
Reason: The interaction with FtsQ is well-documented but "protein binding" is uninformative. Should be annotated with a more specific term or with extension indicating the interacting partner. However, no suitable GO term exists for "divisome protein binding" so keeping with IPI to specific protein is acceptable.
Proposed replacements: protein binding
Supporting Evidence:
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
GO:0005515 protein binding
IPI
PMID:15774864
Interaction network among Escherichia coli membrane proteins... 		ACCEPT
Summary: FtsI interacts with FtsW (P0ABG4) as shown by bacterial two-hybrid analysis [PMID:15774864]. FtsW-FtsI form a core subcomplex of the divisome.
Reason: The FtsI-FtsW interaction is essential for divisome function. FtsW is the lipid II transporter and glycosyltransferase that works with FtsI [PMID:20847002].
Supporting Evidence:
PMID:20847002
The integral membrane FtsW protein and peptidoglycan synthase PBP3 form a subcomplex in Escherichia coli
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
GO:0005515 protein binding
IPI
PMID:15774864
Interaction network among Escherichia coli membrane proteins... 		ACCEPT
Summary: FtsI interacts with FtsL (P0AEN4) per bacterial two-hybrid [PMID:15774864].
Reason: FtsL is an essential divisome protein that interacts with FtsI within the FtsQLB complex.
Supporting Evidence:
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
GO:0005515 protein binding
IPI
PMID:15774864
Interaction network among Escherichia coli membrane proteins... 		ACCEPT
Summary: FtsI interacts with FtsN (P29131) per bacterial two-hybrid [PMID:15774864]. FtsI is required for FtsN localization to the septum.
Reason: FtsN is recruited to the septum by FtsI [PMID:9282742]. This interaction is functionally important.
Supporting Evidence:
PMID:9282742
FtsN, a late recruit to the septum in Escherichia coli
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
GO:0005515 protein binding
IPI
PMID:15774864
Interaction network among Escherichia coli membrane proteins... 		ACCEPT
Summary: FtsI interacts with YmgF (P58034) per bacterial two-hybrid [PMID:15774864].
Reason: YmgF is a small membrane protein that associates with the divisome.
Supporting Evidence:
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
GO:0005515 protein binding
IPI
PMID:17185541
Three functional subdomains of the Escherichia coli FtsQ pro... 		ACCEPT
Summary: FtsI interacts with FtsQ (P06136). Study mapped the FtsQ domains involved in interactions with divisome proteins [PMID:17185541].
Reason: Independent confirmation of FtsI-FtsQ interaction using domain mapping.
Supporting Evidence:
PMID:17185541
FtsQ, an essential protein for the Escherichia coli divisome assembly, is able to interact with various division proteins, namely FtsI, FtsL, FtsN, FtsB and FtsW
GO:0005515 protein binding
IPI
PMID:17185541
Three functional subdomains of the Escherichia coli FtsQ pro... 		ACCEPT
Summary: Cross-species interaction between E. coli FtsI and S. pneumoniae DivIB.
Reason: Xenologous interaction supporting functional conservation of divisome protein interactions.
Supporting Evidence:
PMID:17185541
Three functional subdomains of the Escherichia coli FtsQ protein are involved in its interaction with the other division proteins.
GO:0005515 protein binding
IPI
PMID:17938168
The essential cell division protein FtsN interacts with the ... 		ACCEPT
Summary: FtsI interacts with FtsN per [PMID:17938168]. The study examined FtsN interactions with peptidoglycan synthases.
Reason: Additional evidence for FtsI-FtsN interaction.
Supporting Evidence:
PMID:17938168
2007 Oct 15. The essential cell division protein FtsN interacts with the murein (peptidoglycan) synthase PBP1B in Escherichia coli.
GO:0005515 protein binding
IPI
PMID:18165305
The monofunctional glycosyltransferase of Escherichia coli l... 		ACCEPT
Summary: FtsI (PBP3) interacts with PBP1B (P02919/mrcB). PBP1B is a bifunctional Class A PBP with both glycosyltransferase and transpeptidase activity [PMID:18165305].
Reason: PBP1B localizes to the septum and works with FtsI in septal peptidoglycan synthesis. This interaction is functionally important.
Supporting Evidence:
PMID:28233869
In E. coli, the complex formed by PBP1b, PBP3 and FtsW constitutes the core-enzyme of the divisome
PMID:18165305
The monofunctional glycosyltransferase of Escherichia coli localizes to the cell division site and interacts with penicillin-binding protein 3, FtsW, and FtsN.
GO:0005515 protein binding
IPI
PMID:18165305
The monofunctional glycosyltransferase of Escherichia coli l... 		ACCEPT
Summary: FtsI interacts with MtgA (P46022), the monofunctional glycosyltransferase [PMID:18165305].
Reason: MtgA localizes to the division site and interacts with PBP3, FtsW, and FtsN, suggesting a role in septal peptidoglycan synthesis.
Supporting Evidence:
PMID:18165305
The monofunctional peptidoglycan glycosyltransferase (MtgA) catalyzes glycan chain elongation... is able to interact with three constituents of the divisome, PBP3, FtsW, and FtsN
GO:0005515 protein binding
IPI
PMID:18978050
Characterization of YmgF, a 72-residue inner membrane protei... 		ACCEPT
Summary: FtsI interacts with FtsL. Study characterized YmgF and its association with the division machinery [PMID:18978050].
Reason: Additional evidence for FtsI-FtsL interaction.
Supporting Evidence:
PMID:18978050
Characterization of YmgF, a 72-residue inner membrane protein that associates with the Escherichia coli cell division machinery.
GO:0005515 protein binding
IPI
PMID:18978050
Characterization of YmgF, a 72-residue inner membrane protei... 		ACCEPT
Summary: FtsI interacts with YmgF [PMID:18978050].
Reason: YmgF is a component of the E. coli cell division machinery.
Supporting Evidence:
PMID:18978050
Characterization of YmgF, a 72-residue inner membrane protein that associates with the Escherichia coli cell division machinery.
GO:0005515 protein binding
IPI
PMID:19458048
Crystal structure of the membrane-bound bifunctional transgl... 		ACCEPT
Summary: FtsI interacts with PBP1B. Crystal structure study of PBP1b [PMID:19458048].
Reason: Supports FtsI-PBP1B interaction.
Supporting Evidence:
PMID:19458048
Crystal structure of the membrane-bound bifunctional transglycosylase PBP1b from Escherichia coli.
GO:0005515 protein binding
IPI
PMID:20847002
The integral membrane FtsW protein and peptidoglycan synthas... 		ACCEPT
Summary: FtsI forms a subcomplex with FtsW. FRET and co-immunoprecipitation experiments confirmed direct interactions [PMID:20847002].
Reason: Key evidence for the FtsI-FtsW subcomplex. This is a core interaction for divisome function.
Supporting Evidence:
PMID:20847002
In this work we show direct interactions between FtsW and PBP3 in vivo and in vitro by FRET (FΓΆrster resonance energy transfer) and co-immunoprecipitation experiments
GO:0005515 protein binding
IPI
PMID:22885295
The Ξ²-lactam resistance protein Blr, a small membrane polype... 		ACCEPT
Summary: FtsI interacts with FtsL. Study on Blr protein and the division machinery [PMID:22885295].
Reason: Additional evidence for FtsI-FtsL interaction.
Supporting Evidence:
PMID:22885295
The Ξ²-lactam resistance protein Blr, a small membrane polypeptide, is a component of the Escherichia coli cell division machinery.
GO:0005515 protein binding
IPI
PMID:24561554
The binary protein-protein interaction landscape of Escheric... 		ACCEPT
Summary: FtsI interacts with MtgA. Large-scale binary protein-protein interaction study [PMID:24561554].
Reason: High-throughput confirmation of FtsI-MtgA interaction.
Supporting Evidence:
PMID:24561554
Here we performed yeast two-hybrid screens of 3,305 baits against 3,606 preys
GO:0000917 division septum assembly
NAS
PMID:28419603
Assembly and activation of the Escherichia coli divisome. 		ACCEPT
Summary: FtsI is part of the divisome complex that assembles the division septum. Review article [PMID:28419603].
Reason: Appropriate biological process annotation based on review summarizing extensive experimental literature.
Supporting Evidence:
PMID:28419603
Cell division in Escherichia coli is mediated by a large protein complex called the divisome
GO:0005886 plasma membrane
NAS
PMID:28419603
Assembly and activation of the Escherichia coli divisome. 		ACCEPT
Summary: FtsI localizes to the plasma membrane via its N-terminal transmembrane anchor.
Reason: Correct localization annotation.
Supporting Evidence:
PMID:28419603
Assembly and activation of the Escherichia coli divisome.
GO:0032153 cell division site
NAS
PMID:28419603
Assembly and activation of the Escherichia coli divisome. 		ACCEPT
Summary: FtsI localizes to the cell division site (septum) during cell division.
Reason: Appropriate cellular component annotation supported by experimental evidence [PMID:9603865].
Supporting Evidence:
PMID:9603865
FtsI and FtsW are localized to the septum in Escherichia coli
PMID:28419603
Assembly and activation of the Escherichia coli divisome.
GO:0043093 FtsZ-dependent cytokinesis
NAS
PMID:28419603
Assembly and activation of the Escherichia coli divisome. 		ACCEPT
Summary: FtsI functions in FtsZ-dependent cell division as part of the divisome.
Reason: Appropriate biological process. FtsI localization depends on FtsZ.
Supporting Evidence:
PMID:9603865
The localization of FtsI was not observed in ftsZ or ftsA mutants
PMID:28419603
Assembly and activation of the Escherichia coli divisome.
GO:0051301 cell division
NAS
PMID:28419603
Assembly and activation of the Escherichia coli divisome. 		ACCEPT
Summary: FtsI is essential for cell division.
Reason: Core biological process for FtsI.
Supporting Evidence:
PMID:28419603
Assembly and activation of the Escherichia coli divisome.
GO:0005515 protein binding
IPI
PMID:33895137
ZapG (YhcB/DUF1043), a novel cell division protein in gamma-... 		ACCEPT
Summary: FtsI interacts with ZapG (YhcB, P0ADW3). ZapG is a novel cell division protein linking the Z-ring to septal peptidoglycan synthesis [PMID:33895137].
Reason: ZapG interacts with multiple divisome components including FtsI, linking the Z-ring scaffold to peptidoglycan synthesis machinery.
Supporting Evidence:
PMID:33895137
ZapG (YhcB/DUF1043), a novel cell division protein in gamma-proteobacteria linking the Z-ring to septal peptidoglycan synthesis
GO:0005515 protein binding
IPI
PMID:28233869
Interplay between Penicillin-binding proteins and SEDS prote... 		ACCEPT
Summary: FtsI (PBP3) interacts with FtsW as part of a ternary complex with PBP1b [PMID:28233869]. The study characterized the interplay between these proteins in peptidoglycan synthesis.
Reason: Key evidence showing FtsW-PBP3-PBP1b form a ternary complex essential for divisome function.
Supporting Evidence:
PMID:28233869
PBP3 forms a complex with FtsW and its specific transpeptidase activity is essential for cell division
GO:0009252 peptidoglycan biosynthetic process
RCA
PMID:27525505
SEDS proteins are a widespread family of bacterial cell wall... 		ACCEPT
Summary: FtsI participates in peptidoglycan biosynthesis as the transpeptidase that cross-links glycan strands during cell division [PMID:27525505].
Reason: Core biological process. The SEDS paper confirms Class B PBPs like FtsI provide transpeptidase activity for cross-linking.
Supporting Evidence:
PMID:27525505
cross-linking of adjacent glycan strands is likely carried out by the essential Class B PBPs (for simplicity, bPBPs), which have TP domains
GO:0008955 peptidoglycan glycosyltransferase activity
IMP
PMID:6450748
Evidence for involvement of penicillin-binding protein 3 in ... 		REMOVE
Summary: INCORRECT ANNOTATION. This 1981 paper predates the discovery that Class B PBPs lack glycosyltransferase activity. The glycosyltransferase activity detected was likely due to contaminating Class A PBPs or the associated SEDS protein FtsW. UniProt explicitly cautions this is an error.
Reason: Historical misattribution. Modern evidence [PMID:27525505] clearly shows Class B PBPs like FtsI lack glycosyltransferase activity. The SEDS protein FtsW (which forms a complex with FtsI) provides this activity. UniProt CAUTION states: "Was originally thought to be a bifunctional enzyme with transglycosylase and transpeptidase activities."
Supporting Evidence:
PMID:27525505
the essential Class B PBPs (for simplicity, bPBPs), which have TP domains but lack PGT activity
PMID:6450748
Evidence for involvement of penicillin-binding protein 3 in murein synthesis during septation but not during cell elongation.
GO:0005515 protein binding
IPI
PMID:20497333
Direct interactions of early and late assembling division pr... 		ACCEPT
Summary: FtsI interacts with FtsN. FRET study on divisome protein interactions [PMID:20497333].
Reason: Evidence for FtsI-FtsN interaction.
Supporting Evidence:
PMID:20497333
Epub 2010 May 19. Direct interactions of early and late assembling division proteins in Escherichia coli cells resolved by FRET.
GO:0032153 cell division site
IDA
PMID:9603865
FtsI and FtsW are localized to the septum in Escherichia col... 		ACCEPT
Summary: FtsI was shown to localize to the septum by immunofluorescence microscopy [PMID:9603865].
Reason: Core cellular component annotation. Direct experimental evidence (IDA) from immunofluorescence microscopy.
Supporting Evidence:
PMID:9603865
The localization of FtsI (PBP3), a penicillin-binding protein specifically required for cell division in Escherichia coli, was investigated by immunofluorescence microscopy and found to localize to the septum
GO:0008658 penicillin binding
IDA
PMID:1103132
Distinct penicillin binding proteins involved in the divisio... 		ACCEPT
Summary: Spratt 1975 demonstrated that beta-lactam antibiotics that specifically inhibit cell division bind to PBP3 (FtsI) [PMID:1103132].
Reason: Core molecular function. Classic paper establishing FtsI as a penicillin- binding protein with direct experimental evidence.
Supporting Evidence:
PMID:1103132
Cell division: beta-Lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3 (molecular weight 60,000)
GO:0009410 response to xenobiotic stimulus
IMP
PMID:1103132
Distinct penicillin binding proteins involved in the divisio... 		KEEP AS NON CORE
Summary: FtsI binds beta-lactam antibiotics (xenobiotics), which inhibit its activity and cause cell filamentation [PMID:1103132].
Reason: While accurate that FtsI responds to beta-lactam antibiotics (xenobiotics), this is not a physiological function but rather a pharmacological property. The response is inhibition of division. Keep as non-core annotation.
Supporting Evidence:
PMID:1103132
beta-Lactams that specifically inhibit cell division bind preferentially to penicillin binding protein 3
GO:0051301 cell division
IMP
PMID:1103132
Distinct penicillin binding proteins involved in the divisio... 		ACCEPT
Summary: Temperature-sensitive FtsI mutants fail to divide at non-permissive temperature, demonstrating FtsI is essential for cell division [PMID:1103132].
Reason: Core biological process with strong IMP evidence. Spratt showed that a temperature-sensitive cell division mutant has a thermolabile protein 3.
Supporting Evidence:
PMID:1103132
A temperature-sensitive cell division mutant has been shown to have a thermolabile protein 3
GO:0008955 peptidoglycan glycosyltransferase activity
IDA
PMID:7030331
Peptidoglycan synthetic enzyme activities of highly purified... 		REMOVE
Summary: INCORRECT ANNOTATION. This 1981 paper reported glycosyltransferase activity for purified PBP3, but this was later shown to be incorrect. FtsI is a Class B PBP that lacks glycosyltransferase activity. Any detected activity was likely from contaminating enzymes or the associated FtsW.
Reason: Historical misattribution now known to be incorrect. Class B PBPs lack glycosyltransferase (PGT) activity [PMID:27525505]. UniProt states [PMID:7030331] in its CAUTION that FtsI was "originally thought to be a bifunctional enzyme." The glycosyltransferase activity is provided by SEDS proteins (FtsW) or Class A PBPs (PBP1a, PBP1b), not by FtsI.
Supporting Evidence:
PMID:27525505
the essential Class B PBPs (for simplicity, bPBPs), which have TP domains but lack PGT activity
PMID:7030331
Peptidoglycan synthetic enzyme activities of highly purified penicillin-binding protein 3 in Escherichia coli: a septum-forming reaction sequence.

Core Functions

Septal peptidoglycan cross-linking: FtsI catalyzes the transpeptidation reaction that cross-links peptidoglycan strands specifically at the division septum. It is a D,D-transpeptidase (EC 3.4.16.4) that cleaves D-Ala-D-Ala bonds and forms peptide cross-links. This is the primary enzymatic activity of FtsI [PMID:3531167, PMID:7030331].

Molecular Function:
serine-type D-Ala-D-Ala carboxypeptidase activity

Penicillin binding: FtsI is one of the major penicillin-binding proteins (PBP3). Beta-lactam antibiotics inhibit FtsI by binding to its active site serine, blocking cell division [PMID:1103132]. This property makes FtsI a key antibiotic target.

Molecular Function:
penicillin binding

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000043
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000104
Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:1103132
Distinct penicillin binding proteins involved in the division, elongation, and shape of Escherichia coli K12.
PMID:15774864
Interaction network among Escherichia coli membrane proteins involved in cell division as revealed by bacterial two-hybrid analysis.
PMID:17185541
Three functional subdomains of the Escherichia coli FtsQ protein are involved in its interaction with the other division proteins.
PMID:17938168
The essential cell division protein FtsN interacts with the murein (peptidoglycan) synthase PBP1B in Escherichia coli.
PMID:18165305
The monofunctional glycosyltransferase of Escherichia coli localizes to the cell division site and interacts with penicillin-binding protein 3, FtsW, and FtsN.
PMID:18978050
Characterization of YmgF, a 72-residue inner membrane protein that associates with the Escherichia coli cell division machinery.
PMID:19458048
Crystal structure of the membrane-bound bifunctional transglycosylase PBP1b from Escherichia coli.
PMID:20497333
Direct interactions of early and late assembling division proteins in Escherichia coli cells resolved by FRET.
PMID:20847002
The integral membrane FtsW protein and peptidoglycan synthase PBP3 form a subcomplex in Escherichia coli.
PMID:22885295
The Ξ²-lactam resistance protein Blr, a small membrane polypeptide, is a component of the Escherichia coli cell division machinery.
PMID:24561554
The binary protein-protein interaction landscape of Escherichia coli.
PMID:27525505
SEDS proteins are a widespread family of bacterial cell wall polymerases.
PMID:28233869
Interplay between Penicillin-binding proteins and SEDS proteins promotes bacterial cell wall synthesis.
PMID:28419603
Assembly and activation of the Escherichia coli divisome.
PMID:33895137
ZapG (YhcB/DUF1043), a novel cell division protein in gamma-proteobacteria linking the Z-ring to septal peptidoglycan synthesis.
PMID:6450748
Evidence for involvement of penicillin-binding protein 3 in murein synthesis during septation but not during cell elongation.
PMID:7030331
Peptidoglycan synthetic enzyme activities of highly purified penicillin-binding protein 3 in Escherichia coli: a septum-forming reaction sequence.
PMID:9603865
FtsI and FtsW are localized to the septum in Escherichia coli.
PMID:2677607
Membrane topology of penicillin-binding protein 3 of Escherichia coli.
PMID:9282742
FtsN, a late recruit to the septum in Escherichia coli.
PMID:9614966
The structure and function of Escherichia coli penicillin-binding protein 3.
PMID:3531167
Activity of penicillin-binding protein 3 from Escherichia coli.
file:ECOLI/ftsI/ftsI-deep-research-falcon.md
Deep research on ftsI function

Deep Research

Falcon

(ftsI-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 22 citations 2025-12-23T14:14:29.054485

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research plan and verification
We verified the target as Escherichia coli K-12 ftsI (pbpB) encoding Penicillin-binding protein 3 (PBP3), UniProt P0AD68. PBP3 is the essential class B penicillin-binding protein (bPBP) that provides D,D-transpeptidase activity for septal peptidoglycan (sPG) synthesis during division; it operates with the SEDS glycosyltransferase FtsW in the core divisome complex, and is activated by the FtsQ–FtsB–FtsL (FtsQLB) regulators and FtsN, matching the family/domain annotations provided (transpeptidase/PBP) (https://www.uniprot.org/uniprotkb/P0AD68/entry, database reference; mechanistic/structural details below) (yang2024structuralinsightsinto pages 1-3, cameron2024insightsintothe pages 16-18).

1) Key concepts and definitions with current understanding
- Molecular identity and role: FtsI (PBP3) is the monofunctional, membrane-anchored class B PBP that catalyzes D,D-transpeptidation to form 4β†’3 peptide crosslinks in sPG at midcell during cytokinesis. It has an N-terminal transmembrane helix, a periplasmic β€œpedestal” domain that interfaces with divisome regulators, and a C-terminal transpeptidase domain that harbors the canonical serine-active-site motifs (SXXK, SXN, KTG) conserved across Gram-negatives (illustrated for FtsI orthologs; catalytic Ser is acylated by substrate/Ξ²-lactams) (Cell Discovery, 2024; URL: https://doi.org/10.1038/s41421-023-00629-w; Nature Rev Microbiol, 2024; URL: https://doi.org/10.1038/s41579-023-00942-x; additional motif detail from ortholog structural work) (yang2024structuralinsightsinto pages 1-3, cameron2024insightsintothe pages 16-18, oladele2025impactofsingle pages 37-42).
- Cellular localization and complex: FtsI localizes to the septal ring (Z-ring region) as part of the late-assembling divisome, functioning within the FtsW–FtsI synthase module that executes sPG polymerization (FtsW) and crosslinking (FtsI). FtsQLB binds and stabilizes the complex and transduces activation signals, while FtsN is the late essential activator that triggers robust sPG synthesis. These interaction and activation relationships are established in recent structural and review work (Cell Discovery, 2024; Nature Rev Microbiol, 2024) (yang2024structuralinsightsinto pages 1-3, cameron2024insightsintothe pages 16-18).
- Essentiality: FtsI/PBP3 is essential for cell division in E. coli; loss of function blocks septation and leads to filamentation (summarized in divisome reviews; functional genetics cited therein). Crosslinking studies in Salmonella emphasize the conserved divisome composition and occupancy competition by FtsI paralogs, underscoring the central divisome role of bPBP TPases (Molecular Microbiology, 2024; URL: https://doi.org/10.1111/mmi.15309) (cameron2024insightsintothe pages 16-18, castanheira2024invivocross‐linking pages 22-22).

Catalytic mechanism and substrate specificity
- Reaction: FtsI is a D,D-transpeptidase that forms 4β†’3 crosslinks by transferring the terminal D-Ala-containing acyl donor (stem peptide attached to glycan) to an acceptor stem peptide (D-Ala–meso-DAP in E. coli), via a covalent acyl-enzyme at the catalytic serine, then deacylation to complete crosslink formation (conserved PBP mechanism; motifs SXXK/SXN/KTG). Structural and biochemical data from PBP3 orthologs define the catalytic serine acylation by Ξ²-lactams and substrate (examples compiled in recent literature) (oladele2025impactofsingle pages 37-42, cameron2024insightsintothe pages 16-18).

2) Recent developments and latest research (2023–2024 priority)
- Cryo-EM divisome architecture and activation: A 2024 cryo-EM structure of a FtsW–FtsI–FtsQLB complex (from Pseudomonas; homologous to E. coli) resolved the SEDS–bPBP core and regulator interfaces. It shows FtsI’s pedestal contacting FtsBL coiled coil and FtsW’s ECL4/H2 being stabilized by FtsL, rationalizing how FtsQLB promotes the active conformation of FtsWI and supporting conserved SEDS–bPBP architecture across species (Cell Discovery, 2024; 3.3 Γ…; URL: https://doi.org/10.1038/s41421-023-00629-w) (yang2024structuralinsightsinto pages 1-3).
- Division activation models: Nature Reviews Microbiology (2024) synthesizes evidence that FtsN triggers an activation cascade via FtsQLB to stimulate FtsWI activity, consolidating genetic and structural data, and highlights prior FtsI mutations affecting FtsN recruitment and divisome function (URL: https://doi.org/10.1038/s41579-023-00942-x) (cameron2024insightsintothe pages 16-18).
- FtsN dynamics at septa: Single-molecule and imaging work (bioRxiv preprint 2024) in E. coli reports that FtsN partitions between a synthesis track (with active FtsWI) and a denuded-glycan track coordinating hydrolases, consistent with an activation role for FtsN engaging FtsL/FtsI to stimulate sPG synthesis (bioRxiv 2024; URL: https://doi.org/10.1101/2024.05.13.594014) ().
- Divisome movement paradigms: High-resolution live-cell studies in Gram-positives show that processive movement of septal synthases is driven by PG synthesis rather than FtsZ treadmilling, with emerging two-track models in Gram-negatives; these reinforce that active bPBP TPases like FtsI operate within multimeric synthase complexes coordinated by regulators (Nature Microbiol, 2024; URL: https://doi.org/10.1038/s41564-024-01650-9) (whitley2024peptidoglycansynthesisdrives pages 1-2).

3) Current applications and real-world implementations
- Clinical targeting: Ξ²-Lactam antibiotics target PBP3 (FtsI) among other PBPs; aztreonam is classically PBP3-selective in Enterobacterales, and cefiderocol shows primary interaction with PBP3 with additional PBP engagement. A large European surveillance demonstrated high cefiderocol susceptibility among Enterobacterales (including E. coli) and highlighted frequent ftsI mutations among cefiderocol-resistant isolates, linking PBP3 alterations to clinical resistance (Microbiology Spectrum, 2024; URL: https://doi.org/10.1128/spectrum.04181-23) (henriksen2024invitroactivitya pages 1-2).
- Ξ²-Lactamase inhibitor combinations: Aztreonam–avibactam (ATM–AVI) restores activity against metallo-Ξ²-lactamase (MBL)-producing Enterobacterales and is EMA-approved; however, emergent resistance patterns often involve target modification, including PBP3 (ftsI) changes, especially in conjunction with permeability/efflux alterations (Pharmacotherapy, 2024; URL: https://doi.org/10.1002/phar.4629) ().

4) Expert opinions and analysis from authoritative sources
- Divisome regulation consensus: Cameron and Margolin (Nature Reviews Microbiology, 2024) consolidate that FtsI/PBP3 operates as the septal TPase of the FtsW–FtsI synthase; FtsQLB and FtsN are core activators, and specific FtsI substitutions disrupt septal localization and FtsN recruitment. The review integrates structural advances (FtsWIQLB), genetic activation (β€œsuperfission” alleles), and SPOR-domain targeting to sPG, reflecting field consensus on divisome activation logic (URL: https://doi.org/10.1038/s41579-023-00942-x) (cameron2024insightsintothe pages 16-18).
- Structural mechanisms of core synthase: The 2024 cryo-EM FtsWIQLB structure provides a mechanistic model for how FtsQLB stabilizes the active state of the SEDS–bPBP synthase, with conserved features applicable to E. coli FtsI and supporting the regulator-bridged activation concept (Cell Discovery, 2024; URL: https://doi.org/10.1038/s41421-023-00629-w) (yang2024structuralinsightsinto pages 1-3).

5) Relevant statistics and data from recent studies (2023–2024)
- Cefiderocol surveillance across Enterobacterales (Europe, 2020 collection; reported 2024): 1,909 isolates total (970 Klebsiella, 382 E. coli, 244 Enterobacter). Overall cefiderocol susceptibility 98.1% across Enterobacterales; in meropenem-resistant Enterobacterales (n=148) susceptibility 87.8%. Among cefiderocol-resistant Enterobacterales (n=37), 24/37 (64.9%) harbored ftsI (PBP3) mutations in addition to iron-uptake pathway mutations and carbapenemases, implicating target modification in resistance (Microbiology Spectrum, 2024; Aug 2024 online) (henriksen2024invitroactivitya pages 1-2).
- Mechanistic inhibition metrics for PBPs: Methodological advances have enabled live-cell determination of kinact/KI for PBP inhibition by Ξ²-lactams using activity-based probes, refining potency metrics beyond IC50 for covalent inhibitors; though demonstrated in S. pneumoniae, the approach generalizes to PBP families including E. coli PBPs (ACS Infectious Diseases, 2024; Dec 2024; URL: https://doi.org/10.1021/acsinfecdis.4c00370) ().

Biochemical pathway and interaction map (concise)
- FtsZ/FtsA early assembly β†’ recruitment of FtsK β†’ FtsQLB β†’ FtsW–FtsI assembly at midcell β†’ arrival of FtsN, which binds FtsL/FtsI and activates FtsWI synthase to initiate robust sPG synthesis; amidase activation (FtsEX–EnvC–AmiB) coordinates sPG hydrolysis with synthesis. FtsI’s pedestal engages FtsBL; FtsI transpeptidase executes crosslinking of nascent sPG produced by FtsW (Nature Rev Microbiol, 2024; Cell Discovery, 2024; PLoS Biology, 2024 for FtsEX–EnvC activation) (cameron2024insightsintothe pages 16-18, yang2024structuralinsightsinto pages 1-3).

Subcellular location
- Periplasmic enzyme tethered to the inner membrane by an N-terminal TM helix; catalysis occurs in the periplasm at the septal ring where the divisome assembles (structural review and cryo-EM complex) (yang2024structuralinsightsinto pages 1-3, cameron2024insightsintothe pages 16-18).

Inhibitors and substrate specificity
- Substrate: pentapeptide stems terminating in D-Ala–D-Ala on Lipid II–derived glycan strands; acceptor stems (D-Ala–meso-DAP) are crosslinked via the FtsI acyl-enzyme intermediate. Inhibitors: Ξ²-lactams including aztreonam (PBP3-selective monobactam) and cefiderocol (catechol-siderophore cephalosporin with primary PBP3 engagement in Enterobacterales). Resistance mechanisms increasingly involve target-site modifications in ftsI alongside porin/efflux and Ξ²-lactamases (Microbiology Spectrum, 2024; Pharmacotherapy, 2024) (henriksen2024invitroactivitya pages 1-2).

Recent resistance mechanisms involving ftsI
- Clinical datasets associate ftsI mutations with cefiderocol resistance in Enterobacterales. Surveillance identified ftsI mutations in 24/37 cefiderocol-resistant isolates and multiple iron uptake mutations, often alongside carbapenemases (Microbiology Spectrum, 2024; URL: https://doi.org/10.1128/spectrum.04181-23) (henriksen2024invitroactivitya pages 1-2).
- Reviews of Ξ²-lactam/Ξ²-lactamase inhibitor therapy note that resistance to aztreonam–avibactam can involve PBP3 changes (ftsI), especially in co-presence of permeability defects/ESBLs/MBLs, underscoring PBP3 as a key adaptive target (Pharmacotherapy, 2024; URL: https://doi.org/10.1002/phar.4629) ().

Notes on protein family/domains
- FtsI is a class B PBP (transpeptidase family). The pedestal domain mediates interactions with FtsBL; the catalytic TPase domain bears SXXK/SXN/KTG motifs of serine TPases. The recent FtsWIQLB structure confirms these domain organizations and interfacial contacts consistent with transpeptidase/PBP_dimer superfamily folds described in UniProt (Cell Discovery, 2024) (yang2024structuralinsightsinto pages 1-3).

Conclusion
The E. coli K-12 ftsI gene encodes PBP3, the essential septal D,D-transpeptidase of the divisome. Its periplasmic catalytic domain performs 4β†’3 crosslinking on nascent septal PG synthesized by FtsW. Activation is mediated by FtsQLB and FtsN, as supported by 2024 cryo-EM of the FtsWIQLB complex and synthesis-focused reviews. Clinically, PBP3 is a principal target of Ξ²-lactams; aztreonam and cefiderocol maintain activity against many resistant Enterobacterales, though emerging resistance frequently includes ftsI mutations, highlighting the translational importance of PBP3-focused surveillance and inhibitor design (yang2024structuralinsightsinto pages 1-3, cameron2024insightsintothe pages 16-18, henriksen2024invitroactivitya pages 1-2).

Citations with URLs and dates
- Yang L et al., Structural insights into the activation of the divisome complex FtsWIQLB, Cell Discovery, 2024-01-11. URL: https://doi.org/10.1038/s41421-023-00629-w (yang2024structuralinsightsinto pages 1-3).
- Cameron TA, Margolin W., Insights into the assembly and regulation of the bacterial divisome, Nature Reviews Microbiology, 2024-07. URL: https://doi.org/10.1038/s41579-023-00942-x (cameron2024insightsintothe pages 16-18).
- Henriksen AS et al., In vitro activity of cefiderocol against European Enterobacterales…, Microbiology Spectrum, 2024-08. URL: https://doi.org/10.1128/spectrum.04181-23 (henriksen2024invitroactivitya pages 1-2).
- Lyu Z et al., E. coli FtsN coordinates synthesis and degradation of sPG…, bioRxiv, 2024-08-01 (preprint). URL: https://doi.org/10.1101/2024.05.13.594014 ().
- Chen Y et al., Structure and activity of the septal peptidoglycan hydrolysis machinery…, PLOS Biology, 2024-05-22. URL: https://doi.org/10.1371/journal.pbio.3002628 ().
- Whitley KD et al., Peptidoglycan synthesis drives a single population of septal synthases…, Nature Microbiology, 2024-03-18. URL: https://doi.org/10.1038/s41564-024-01650-9 (whitley2024peptidoglycansynthesisdrives pages 1-2).
- Musawa MA et al., Aztreonam–avibactam: The dynamic duo…, Pharmacotherapy, 2024-11-29. URL: https://doi.org/10.1002/phar.4629 ().
- Castanheira S et al., In Vivo Cross-Linking Sheds Light on the Salmonella Divisome…, Molecular Microbiology, 2024-09-06. URL: https://doi.org/10.1111/mmi.15309 (castanheira2024invivocross‐linking pages 22-22).
- Shirley JD et al., kinact/KI Value Determination for PBPs in Live Cells, ACS Infectious Diseases, 2024-12-06. URL: https://doi.org/10.1021/acsinfecdis.4c00370 ().
- Additional catalytic motif/active-site context (ortholog): Oladele OE, Impact of substitutions in FtsI…, 2025 (structural motif conservation and Ξ²-lactam complexes summarized) (oladele2025impactofsingle pages 37-42).

References

  1. (yang2024structuralinsightsinto pages 1-3): Lili Yang, Yujiao Chen, Shenghai Chang, Chongrong Shen, Xin Wang, Changbin Zhang, Zhibo Zhang, Bi-Sen Ding, Zhaoming Su, Haohao Dong, and Xiaodi Tang. Structural insights into the activation of the divisome complex ftswiqlb. Cell Discovery, Jan 2024. URL: https://doi.org/10.1038/s41421-023-00629-w, doi:10.1038/s41421-023-00629-w. This article has 11 citations and is from a peer-reviewed journal.

  2. (cameron2024insightsintothe pages 16-18): Todd A. Cameron and William Margolin. Insights into the assembly and regulation of the bacterial divisome. Nature Reviews Microbiology, 22:33-45, Jul 2024. URL: https://doi.org/10.1038/s41579-023-00942-x, doi:10.1038/s41579-023-00942-x. This article has 105 citations and is from a highest quality peer-reviewed journal.

  3. (oladele2025impactofsingle pages 37-42): OE Oladele. Impact of single substitution mutations in conserved n-terminal residues of ftsi on penicillin binding and ftsw interaction in neisseria gonorrhoeae. Unknown journal, 2025.

  4. (castanheira2024invivocross‐linking pages 22-22): SΓ³nia Castanheira, David LΓ³pez‐Escarpa, Alberto Paradela, and Francisco GarcΓ­a‐del Portillo. In vivo cross‐linking sheds light on the salmonella divisome in which pbp3 and pbp3sal compete for occupancy. Molecular Microbiology, 122:797-818, Sep 2024. URL: https://doi.org/10.1111/mmi.15309, doi:10.1111/mmi.15309. This article has 4 citations and is from a domain leading peer-reviewed journal.

  5. (whitley2024peptidoglycansynthesisdrives pages 1-2): Kevin D. Whitley, James Grimshaw, David M. Roberts, Eleni Karinou, Phillip J. Stansfeld, and SΓ©amus Holden. Peptidoglycan synthesis drives a single population of septal cell wall synthases during division in bacillus subtilis. Nature Microbiology, 9:1064-1074, Mar 2024. URL: https://doi.org/10.1038/s41564-024-01650-9, doi:10.1038/s41564-024-01650-9. This article has 19 citations and is from a highest quality peer-reviewed journal.

  6. (henriksen2024invitroactivitya pages 1-2): Anne Santerre Henriksen, Fabio Arena, Marie Attwood, Rafael Canton, SΓΆren Gatermann, Thierry Naas, Ian Morrissey, Christopher Longshaw, Birgit Willinger, David Leyssene, Christian Cattoen, Corentine Alauzet, Pierre Boyer, VΓ©ronique Dubois, Katy Jeannot, Stephane Corvec, Alix Pantel, Thomas Guillard, Audrey Merens Gontier, Thierry Naas, Holger Rohde, Stefan Ziesing, Can Imirzalioglu, Klaus-Peter Hunfeld, Jette Jung, SΓΆren Gatermann, Mathias Pletz, Gabriele Bianco, Anna Giammanco, Davide Carcione, Giammarco Raponi, Caterina Matinato, Enea Gino Di Domenico, Paolo Gaibani, Anna Marchese, Fabio Arena, Claudia Niccolai, Stefania Stefani, Cristina Pitart, Jose Luis Barrios, Emilia Cercenado, German Bou, Alicia Beteta Lopez, Rafael Canton, Jose Lopez Hontangas, Irene Gracia-Ahufinger, Antonio Oliver, Lorena Lopez-Cerero, Nieves Larrosa, David Wareham, John Perry, Anna Casey, Jasvir Nahl, Daniel Hughes, Michael Coyne, Michelle Lister, and Marie Attwood. in vitro activity of cefiderocol against european enterobacterales, including isolates resistant to meropenem and recentΞ²-lactam/Ξ²-lactamase inhibitor combinations. Microbiology Spectrum, Aug 2024. URL: https://doi.org/10.1128/spectrum.04181-23, doi:10.1128/spectrum.04181-23. This article has 15 citations and is from a domain leading peer-reviewed journal.

Citations

  1. yang2024structuralinsightsinto pages 1-3
  2. cameron2024insightsintothe pages 16-18
  3. whitley2024peptidoglycansynthesisdrives pages 1-2
  4. henriksen2024invitroactivitya pages 1-2
  5. oladele2025impactofsingle pages 37-42
  6. https://www.uniprot.org/uniprotkb/P0AD68/entry,
  7. https://doi.org/10.1038/s41421-023-00629-w;
  8. https://doi.org/10.1038/s41579-023-00942-x;
  9. https://doi.org/10.1111/mmi.15309
  10. https://doi.org/10.1038/s41421-023-00629-w
  11. https://doi.org/10.1038/s41579-023-00942-x
  12. https://doi.org/10.1101/2024.05.13.594014
  13. https://doi.org/10.1038/s41564-024-01650-9
  14. https://doi.org/10.1128/spectrum.04181-23
  15. https://doi.org/10.1002/phar.4629
  16. https://doi.org/10.1021/acsinfecdis.4c00370
  17. https://doi.org/10.1371/journal.pbio.3002628
  18. https://doi.org/10.1038/s41421-023-00629-w,
  19. https://doi.org/10.1038/s41579-023-00942-x,
  20. https://doi.org/10.1111/mmi.15309,
  21. https://doi.org/10.1038/s41564-024-01650-9,
  22. https://doi.org/10.1128/spectrum.04181-23,

πŸ“š Additional Documentation

Bioreason Rl Predictions

(ftsI-bioreason-rl-predictions.md)

BioReason Chat Export

Exported on March 22, 2026 at 02:18 AM

Organism: Escherichia coli

Sequence:

MKAAAKTQKPKRQEEHANFISWRFALLCGCILLALAFLLGRVAWLQVISPDMLVKEGDMRSLRVQQVSTSRGMITDRSGRPLAVSVPVKAIWADPKEVHDAGGISVGDRWKALANALNIPLDQLSARINANPKGRFIYLARQVNPDMADYIKKLKLPGIHLREESRRYYPSGEVTAHLIGFTNVDSQGIEGVEKSFDKWLTGQPGERIVRKDRYGRVIEDISSTDSQAAHNLALSIDERLQALVYRELNNAVAFNKAESGSAVLVDVNTGEVLAMANSPSYNPNNLSGTPKEAMRNRTITDVFEPGSTVKPMVVMTALQRGVVRENSVLNTIPYRINGHEIKDVARYSELTLTGVLQKSSNVGVSKLALAMPSSALVDTYSRFGLGKATNLGLVGERSGLYPQKQRWSDIERATFSFGYGLMVTPLQLARVYATIGSYGIYRPLSITKVDPPVPGERVFPESIVRTVVHMMESVALPGGGGVKAAIKGYRIAIKTGTAKKVGPDGRYINKYIAYTAGVAPASQPRFALVVVINDPQAGKYYGGAVSAPVFGAIMGGVLRTMNIEPDALTTGDKNEFVINQGEGTGGRS

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the sequence. The N-terminal half carries two tightly aligned signatures for oligomerization and scaffold formation: IPR036138 (Penicillin-binding protein, dimerisation domain superfamily, residues 63–233) and its core IPR005311 (Penicillin-binding protein, dimerisation domain, residues 69–220). This module typically builds a stable dimeric platform that positions catalytic elements and couples to the membrane anchor. The central-to-C-terminal region is dominated by catalytic hallmarks of the class D Ξ²-lactamase/transpeptidase fold: IPR012338 (Beta-lactamase/transpeptidase-like superfamily, residues 235–563) and IPR001460 (Penicillin-binding protein, transpeptidase domain, residues 260–554). These specify the canonical active-site architecture that forms a thioester intermediate with D-Ala-D-Ala and is susceptible to covalent acylation by Ξ²-lactam antibiotics. Two broader family-level envelopes encompass nearly the entire enzyme: IPR050515 (Class D Ξ²-lactamase/transpeptidase family, residues 13–566) and IPR037532 (Peptidoglycan D,D-transpeptidase FtsI family, residues 13–575). Together, these families anchor the assignment to a DD-transpeptidase specialized for late-stage peptidoglycan cross-linking.

This domain architecture causes a precise molecular function. The dimerization domain (IPR005311/IPR036138) organizes the catalytic core (IPR001460/IPR012338) into an active site that performs D,D-transpeptidation on peptidoglycan stem peptidesβ€”formally, DD-transpeptidase chemistry and penicillin binding. The class D transpeptidase scaffold and the conserved catalytic fold predict GO:0008658 penicillin binding as a defining property: Ξ²-lactams acylate and inhibit the active-site serine/thiol chemistry. Thus, the most direct molecular function evidenced here is penicillin binding (GO:0008658), with inhibition arising intrinsically from the transpeptidase mechanism.

From function to process, DD-transpeptidation is the terminal cross-linking step that stabilizes the mature sacculus during septation. The FtsI-family envelope (IPR037532) and the transpeptidase core (IPR001460) collectively tie this enzyme to the late, membrane-proximal phase of cell wall biogenesis and division. Consequently, the biological role converges on peptidoglycan biogenesis and cell division, where cross-linking fortifies the septal wall and coordinates cytokinesis.

Cellular localization follows causally from the need to act on membrane-associated peptidoglycan. The architecture lacks soluble secretion signals and instead implies membrane association via the N-terminal region that precedes the dimerization scaffold. The experimentally grounded placement is the cell inner membrane of a Gram-negative bacterium, which aligns with an integral membrane enzyme that presents its catalytic face to the periplasm. Therefore, the cellular component is the bacterial inner (plasma) membrane.

Mechanistically, I propose the following working model. The N-terminal membrane-proximal platform and dimerization domain assemble a bivalent platform that recruits and stabilizes the catalytic core. At the septum, this enzyme binds Ξ²-lactams (penicillin-binding property) and becomes transiently acylated, which throttles DD-transpeptidation. By forming dimers and coupling to membrane anchors, it concentrates activity at sites of active cross-linking to finalize sacculus maturation. Likely interaction partners include the divisome and elongasome modules at the inner membrane, notably FtsZ/FtsA/SepF assemblies and adjacent peptidoglycan synthases and hydrolases that coordinate septal wall construction.

Functional Summary

An inner-membrane–anchored DD-transpeptidase in Escherichia coli that assembles via an N-terminal dimerization scaffold to present a class D transpeptidase catalytic core that cross-links peptidoglycan during late-stage cell wall construction and cytokinesis. Its active-site chemistry inherently binds Ξ²-lactam antibiotics, which acylate and inhibit the catalytic cycle. By concentrating activity at the division septum, it finalizes sacculus stabilization essential for cell division and envelope integrity at the inner membrane.

UniProt Summary

Peptidoglycan D,D-transpeptidase involved in the late stage of cell wall formation and division.

InterPro Domains

  • Class D beta-lactamase/transpeptidase (IPR050515, family) β€” residues 13-566
  • Peptidoglycan D,D-transpeptidase FtsI (IPR037532, family) β€” residues 13-575
  • Penicillin-binding protein, dimerisation domain superfamily (IPR036138, homologous_superfamily) β€” residues 63-233
  • Penicillin-binding protein, dimerisation domain (IPR005311, domain) β€” residues 69-220
  • Beta-lactamase/transpeptidase-like (IPR012338, homologous_superfamily) β€” residues 235-563
  • Penicillin-binding protein, transpeptidase (IPR001460, domain) β€” residues 260-554

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), protein binding (GO:0005515)

Biological Process: biological_process (GO:0008150), response to stimulus (GO:0050896), cellular process (GO:0009987), response to chemical (GO:0042221), cell division (GO:0051301), response to xenobiotic stimulus (GO:0009410)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), cell periphery (GO:0071944), membrane (GO:0016020), cell division site (GO:0032153), plasma membrane (GO:0005886)

Generated by BioReason

Bioreason Rl Review

(ftsI-bioreason-rl-review.md)

BioReason-Pro RL Review: ftsI (E. coli)

Source: ftsI-bioreason-rl-predictions.md

  • Correctness: 4/5
  • Completeness: 4/5

Functional Summary Review

The BioReason functional summary describes ftsI as:

An inner-membrane-anchored DD-transpeptidase in Escherichia coli that assembles via an N-terminal dimerization scaffold to present a class D transpeptidase catalytic core that cross-links peptidoglycan during late-stage cell wall construction and cytokinesis. Its active-site chemistry inherently binds beta-lactam antibiotics, which acylate and inhibit the catalytic cycle. By concentrating activity at the division septum, it finalizes sacculus stabilization essential for cell division and envelope integrity at the inner membrane.

This is a largely accurate summary. The core functions -- DD-transpeptidation, peptidoglycan cross-linking, beta-lactam binding, septal localization, and role in cell division -- are all correctly identified. The domain architecture analysis correctly identifies the dimerization domain and transpeptidase domain.

Minor issues:
- FtsI is classified as a "class D transpeptidase" in the thinking trace, but it is actually a Class B high-molecular-mass penicillin-binding protein. The IPR050515 family is "Class D beta-lactamase/transpeptidase" which is a superfamily-level classification; the curated review correctly identifies FtsI as Class B.
- The summary does not mention that FtsI is a monofunctional transpeptidase (lacks glycosyltransferase activity). This is significant because the curated review specifically flags the interpro2go annotation for peptidoglycan glycosyltransferase activity (GO:0008955) as INCORRECT for FtsI.
- Does not mention the FtsI-FtsW subcomplex or the broader divisome context (FtsQ, FtsL, FtsN, PBP1b).

The summary correctly identifies the inner membrane anchoring, periplasmic catalytic exposure, and septal localization.

Comparison with interpro2go:

The curated review identifies a key interpro2go error: GO:0008955 (peptidoglycan glycosyltransferase activity) was incorrectly assigned to FtsI via GO_REF:0000002. FtsI is a monofunctional transpeptidase that lacks GT activity; the SEDS protein FtsW provides the glycosyltransferase activity. BioReason does not make this error in its functional summary -- it correctly describes only transpeptidase activity. However, BioReason also does not explicitly predict the correct specific catalytic activity (serine-type D-Ala-D-Ala carboxypeptidase activity, GO:0009002). The model avoids interpro2go's error but does not add much beyond the correct general narrative.

Notes on thinking trace

The trace correctly identifies all six InterPro domains and builds a coherent functional model. The mention of "FtsZ/FtsA/SepF assemblies" as interaction partners is appropriate. The classification as "class D" is an artifact of the IPR050515 superfamily name rather than a biological misclassification.

πŸ“„ View Raw YAML

 
id: P0AD68
gene_symbol: ftsI
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:83333
  label: Escherichia coli (strain K12)
description: FtsI (also known as PBP3/PbpB) is an essential peptidoglycan 
  D,D-transpeptidase required for cell division in E. coli. It is a Class B 
  high-molecular-mass penicillin-binding protein that catalyzes cross-linking of
  peptidoglycan at the division septum. FtsI is a monofunctional transpeptidase 
  - unlike Class A PBPs, it lacks glycosyltransferase activity. FtsI forms a 
  subcomplex with FtsW (a SEDS protein that provides glycosyltransferase 
  activity) and interacts with multiple divisome proteins including FtsQ, FtsL, 
  FtsN, and PBP1b. FtsI localizes to the division septum during later stages of 
  cell growth and throughout septation. Inhibition by beta-lactam antibiotics 
  like penicillin blocks cell division causing filamentation.
existing_annotations:
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FtsI is an integral membrane protein with a single transmembrane 
        helix that anchors it to the plasma membrane. The bulk of the protein 
        protrudes into the periplasmic space [PMID:2677607]. UniProt confirms 
        "Cell inner membrane; Single-pass membrane protein; Periplasmic side."
      action: ACCEPT
      reason: Well-supported by phylogenetic inference (IBA) and consistent with
        the experimentally determined topology of FtsI. The protein contains an 
        N-terminal transmembrane anchor and the periplasmic catalytic domain 
        [PMID:2677607, PMID:9614966].
      supported_by:
        - reference_id: file:ECOLI/ftsI/ftsI-deep-research-falcon.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0008658
      label: penicillin binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FtsI (PBP3) is one of the major penicillin-binding proteins in E.
        coli. Spratt 1975 [PMID:1103132] showed that beta-lactams that 
        specifically inhibit cell division bind preferentially to penicillin 
        binding protein 3.
      action: ACCEPT
      reason: Core function of FtsI. Penicillin binding is essential for the 
        mechanism of action of beta-lactam antibiotics against FtsI. 
        Experimentally demonstrated by IDA [PMID:1103132] and confirmed by IBA 
        phylogenetic inference.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: beta-Lactams that specifically inhibit cell division 
            bind preferentially to penicillin binding protein 3 (molecular 
            weight 60,000)
  - term:
      id: GO:0071555
      label: cell wall organization
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: FtsI participates in peptidoglycan synthesis at the division 
        septum, contributing to cell wall organization during cell division. 
        Botta and Park [PMID:6450748] showed PBP3 activity is required for 
        septal murein synthesis.
      action: ACCEPT
      reason: Appropriate biological process annotation. FtsI functions in cell 
        wall synthesis specifically during septation. The IBA inference is 
        supported by extensive experimental evidence.
      supported_by:
        - reference_id: PMID:6450748
          supporting_text: These results support the hypothesis that PBP-3 
            activity is exclusively required for septal murein synthesis
  - term:
      id: GO:0000917
      label: division septum assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI is essential for division septum assembly. It localizes to 
        the septum and provides the transpeptidase activity necessary for 
        cross-linking peptidoglycan during septation [PMID:9603865, 
        PMID:28419603].
      action: ACCEPT
      reason: Core biological process for FtsI. The IEA annotation based on 
        UniProt keywords is appropriate and supported by extensive experimental 
        evidence from multiple publications.
      supported_by:
        - reference_id: PMID:9603865
          supporting_text: The localization of FtsI (PBP3), a penicillin-binding
            protein specifically required for cell division in Escherichia coli,
            was investigated by immunofluorescence microscopy and found to 
            localize to the septum
        - reference_id: PMID:28419603
          supporting_text: Cell division in Escherichia coli is mediated by a 
            large protein complex called the divisome
  - term:
      id: GO:0004180
      label: carboxypeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI has D,D-transpeptidase activity classified under EC 3.4.16.4
        (serine-type D-Ala-D-Ala carboxypeptidase). This activity involves 
        cleavage of the D-Ala-D-Ala bond and transpeptidation.
      action: ACCEPT
      reason: Appropriate general MF term. FtsI catalyzes the cleavage of the 
        terminal D-alanine from peptidoglycan precursors during 
        transpeptidation, which is a type of carboxypeptidase activity. More 
        specific term GO:0009002 is also annotated.
      supported_by:
        - reference_id: PMID:3531167
          supporting_text: Activity of penicillin-binding protein 3 from 
            Escherichia coli
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation for plasma membrane localization via 
        combined IEA methods. FtsI is a membrane-anchored protein.
      action: ACCEPT
      reason: Correct localization. Duplicates with different evidence codes are
        acceptable as they provide independent support.
  - term:
      id: GO:0006508
      label: proteolysis
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI has peptidase activity (D,D-transpeptidase) that involves 
        cleavage of peptide bonds in peptidoglycan precursors during cell wall 
        synthesis.
      action: KEEP_AS_NON_CORE
      reason: While technically accurate (FtsI cleaves D-Ala-D-Ala bonds), this 
        is a very broad term. The more specific biological process is 
        peptidoglycan biosynthesis, not general proteolysis. Keep as non-core.
  - term:
      id: GO:0008233
      label: peptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI has D,D-transpeptidase activity that involves peptide bond 
        cleavage.
      action: KEEP_AS_NON_CORE
      reason: Accurate but very general. The more specific term GO:0009002 
        (serine-type D-Ala-D-Ala carboxypeptidase activity) is more informative.
        Keep as non-core supporting annotation.
  - term:
      id: GO:0008360
      label: regulation of cell shape
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI is involved in septation-specific peptidoglycan synthesis. 
        While cell division affects cell shape, FtsI is not primarily a 
        shape-regulating protein like PBP2 (which determines rod shape). FtsI 
        specifically functions in division, not elongation.
      action: MARK_AS_OVER_ANNOTATED
      reason: Spratt 1975 [PMID:1103132] showed distinct PBPs for division 
        (PBP3/FtsI), elongation (PBP1), and shape (PBP2). FtsI loss causes 
        filamentation but does not alter cell shape in the way PBP2 mutations 
        do. This annotation conflates division with shape regulation.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: 'Cell shape: beta-Lactams that specifically result in the
            production of ovoid cells bind to penicillin binding protein 2... Cell
            division: beta-Lactams that specifically inhibit cell division bind preferentially
            to penicillin binding protein 3'
  - term:
      id: GO:0008658
      label: penicillin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation for penicillin binding via combined IEA 
        methods.
      action: ACCEPT
      reason: Core molecular function. Duplicates with different evidence 
        sources are acceptable.
  - term:
      id: GO:0008955
      label: peptidoglycan glycosyltransferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'INCORRECT ANNOTATION. FtsI is a Class B PBP that lacks glycosyltransferase
        activity. UniProt explicitly states: "Was originally thought to be a bifunctional
        enzyme with transglycosylase and transpeptidase activities" (CAUTION). The
        SEDS protein FtsW provides the glycosyltransferase activity in the FtsI-FtsW
        complex [PMID:27525505].'
      action: REMOVE
      reason: This is a well-documented error. Meeske et al. 2016 
        [PMID:27525505] clearly state that Class B PBPs "have TP domains but 
        lack PGT activity." The glycosyltransferase activity is provided by SEDS
        proteins (FtsW for division, RodA for elongation), not by Class B PBPs 
        like FtsI. The InterPro mapping that generated this IEA annotation is 
        incorrect for FtsI.
      supported_by:
        - reference_id: PMID:27525505
          supporting_text: Under these conditions, cross-linking of adjacent 
            glycan strands is likely carried out by the essential Class B PBPs 
            (for simplicity, bPBPs), which have TP domains but lack PGT activity
  - term:
      id: GO:0009002
      label: serine-type D-Ala-D-Ala carboxypeptidase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'FtsI catalyzes the transpeptidation reaction that cross-links peptidoglycan
        strands. The EC number 3.4.16.4 describes this activity: "Preferential cleavage:
        (Ac)2-L-Lys-D-Ala-|-D-Ala. Also transpeptidation of peptidyl-alanyl moieties."'
      action: ACCEPT
      reason: Core molecular function of FtsI. This is the primary enzymatic 
        activity that FtsI performs - a serine-type D,D-transpeptidase that 
        cleaves D-Ala-D-Ala bonds and catalyzes transpeptidation to cross-link 
        peptidoglycan.
      supported_by:
        - reference_id: PMID:3531167
          supporting_text: Activity of penicillin-binding protein 3 from 
            Escherichia coli
        - reference_id: PMID:7030331
          supporting_text: Peptidoglycan synthetic enzyme activities of highly 
            purified penicillin-binding protein 3
  - term:
      id: GO:0009252
      label: peptidoglycan biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: FtsI is directly involved in peptidoglycan biosynthesis, 
        specifically the cross-linking step at the division septum 
        [PMID:6450748].
      action: ACCEPT
      reason: Core biological process. FtsI catalyzes the transpeptidation 
        reaction that cross-links peptidoglycan strands during septal cell wall 
        synthesis. This is UniProt pathway annotation (UPA00219).
      supported_by:
        - reference_id: PMID:6450748
          supporting_text: Evidence for involvement of penicillin-binding 
            protein 3 in murein synthesis during septation
  - term:
      id: GO:0016787
      label: hydrolase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: FtsI has hydrolase activity as part of its transpeptidase 
        mechanism (cleavage of D-Ala-D-Ala bonds).
      action: KEEP_AS_NON_CORE
      reason: Very general term. More specific terms like GO:0009002 are more 
        informative. Keep as non-core ancestor term.
  - term:
      id: GO:0043093
      label: FtsZ-dependent cytokinesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: FtsI functions in FtsZ-dependent cell division. FtsI localization
        to the septum requires prior localization of FtsZ [PMID:9603865].
      action: ACCEPT
      reason: Appropriate biological process. FtsI is part of the divisome that 
        assembles on the FtsZ ring scaffold. Localization is dependent on FtsZ 
        [PMID:9603865].
      supported_by:
        - reference_id: PMID:9603865
          supporting_text: The localization of FtsI was not observed in ftsZ or 
            ftsA mutants, indicating that it was dependent on the prior 
            localization of these proteins
  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: FtsI is essential for cell division. Inhibition causes 
        filamentation and cell death [PMID:1103132].
      action: ACCEPT
      reason: Core biological process. FtsI is required for septation and cell 
        division. Well-supported by experimental evidence.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: 'Cell division: beta-Lactams that specifically inhibit
            cell division bind preferentially to penicillin binding protein 3'
  - term:
      id: GO:0071555
      label: cell wall organization
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Duplicate annotation for cell wall organization via UniProt 
        keyword mapping.
      action: ACCEPT
      reason: Appropriate biological process. Duplicates acceptable with 
        different evidence.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15774864
    review:
      summary: FtsI interacts with FtsQ (P06136) as shown by bacterial 
        two-hybrid analysis [PMID:15774864]. FtsQ is an essential divisome 
        protein.
      action: MODIFY
      reason: The interaction with FtsQ is well-documented but "protein binding"
        is uninformative. Should be annotated with a more specific term or with 
        extension indicating the interacting partner. However, no suitable GO 
        term exists for "divisome protein binding" so keeping with IPI to 
        specific protein is acceptable.
      proposed_replacement_terms:
        - id: GO:0005515
          label: protein binding
      supported_by:
        - reference_id: PMID:15774864
          supporting_text: Interaction network among Escherichia coli membrane 
            proteins involved in cell division as revealed by bacterial 
            two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15774864
    review:
      summary: FtsI interacts with FtsW (P0ABG4) as shown by bacterial 
        two-hybrid analysis [PMID:15774864]. FtsW-FtsI form a core subcomplex of
        the divisome.
      action: ACCEPT
      reason: The FtsI-FtsW interaction is essential for divisome function. FtsW
        is the lipid II transporter and glycosyltransferase that works with FtsI
        [PMID:20847002].
      supported_by:
        - reference_id: PMID:20847002
          supporting_text: The integral membrane FtsW protein and peptidoglycan 
            synthase PBP3 form a subcomplex in Escherichia coli
        - reference_id: PMID:15774864
          supporting_text: Interaction network among Escherichia coli membrane 
            proteins involved in cell division as revealed by bacterial 
            two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15774864
    review:
      summary: FtsI interacts with FtsL (P0AEN4) per bacterial two-hybrid 
        [PMID:15774864].
      action: ACCEPT
      reason: FtsL is an essential divisome protein that interacts with FtsI 
        within the FtsQLB complex.
      supported_by:
        - reference_id: PMID:15774864
          supporting_text: Interaction network among Escherichia coli membrane 
            proteins involved in cell division as revealed by bacterial 
            two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15774864
    review:
      summary: FtsI interacts with FtsN (P29131) per bacterial two-hybrid 
        [PMID:15774864]. FtsI is required for FtsN localization to the septum.
      action: ACCEPT
      reason: FtsN is recruited to the septum by FtsI [PMID:9282742]. This 
        interaction is functionally important.
      supported_by:
        - reference_id: PMID:9282742
          supporting_text: FtsN, a late recruit to the septum in Escherichia 
            coli
        - reference_id: PMID:15774864
          supporting_text: Interaction network among Escherichia coli membrane 
            proteins involved in cell division as revealed by bacterial 
            two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15774864
    review:
      summary: FtsI interacts with YmgF (P58034) per bacterial two-hybrid 
        [PMID:15774864].
      action: ACCEPT
      reason: YmgF is a small membrane protein that associates with the 
        divisome.
      supported_by:
        - reference_id: PMID:15774864
          supporting_text: Interaction network among Escherichia coli membrane 
            proteins involved in cell division as revealed by bacterial 
            two-hybrid analysis.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17185541
    review:
      summary: FtsI interacts with FtsQ (P06136). Study mapped the FtsQ domains 
        involved in interactions with divisome proteins [PMID:17185541].
      action: ACCEPT
      reason: Independent confirmation of FtsI-FtsQ interaction using domain 
        mapping.
      supported_by:
        - reference_id: PMID:17185541
          supporting_text: FtsQ, an essential protein for the Escherichia coli 
            divisome assembly, is able to interact with various division 
            proteins, namely FtsI, FtsL, FtsN, FtsB and FtsW
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17185541
    review:
      summary: Cross-species interaction between E. coli FtsI and S. pneumoniae 
        DivIB.
      action: ACCEPT
      reason: Xenologous interaction supporting functional conservation of 
        divisome protein interactions.
      supported_by:
        - reference_id: PMID:17185541
          supporting_text: Three functional subdomains of the Escherichia coli 
            FtsQ protein are involved in its interaction with the other division
            proteins.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17938168
    review:
      summary: FtsI interacts with FtsN per [PMID:17938168]. The study examined 
        FtsN interactions with peptidoglycan synthases.
      action: ACCEPT
      reason: Additional evidence for FtsI-FtsN interaction.
      supported_by:
        - reference_id: PMID:17938168
          supporting_text: 2007 Oct 15. The essential cell division protein FtsN
            interacts with the murein (peptidoglycan) synthase PBP1B in 
            Escherichia coli.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18165305
    review:
      summary: FtsI (PBP3) interacts with PBP1B (P02919/mrcB). PBP1B is a 
        bifunctional Class A PBP with both glycosyltransferase and 
        transpeptidase activity [PMID:18165305].
      action: ACCEPT
      reason: PBP1B localizes to the septum and works with FtsI in septal 
        peptidoglycan synthesis. This interaction is functionally important.
      supported_by:
        - reference_id: PMID:28233869
          supporting_text: In E. coli, the complex formed by PBP1b, PBP3 and 
            FtsW constitutes the core-enzyme of the divisome
        - reference_id: PMID:18165305
          supporting_text: The monofunctional glycosyltransferase of Escherichia
            coli localizes to the cell division site and interacts with 
            penicillin-binding protein 3, FtsW, and FtsN.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18165305
    review:
      summary: FtsI interacts with MtgA (P46022), the monofunctional 
        glycosyltransferase [PMID:18165305].
      action: ACCEPT
      reason: MtgA localizes to the division site and interacts with PBP3, FtsW,
        and FtsN, suggesting a role in septal peptidoglycan synthesis.
      supported_by:
        - reference_id: PMID:18165305
          supporting_text: The monofunctional peptidoglycan glycosyltransferase 
            (MtgA) catalyzes glycan chain elongation... is able to interact with
            three constituents of the divisome, PBP3, FtsW, and FtsN
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18978050
    review:
      summary: FtsI interacts with FtsL. Study characterized YmgF and its 
        association with the division machinery [PMID:18978050].
      action: ACCEPT
      reason: Additional evidence for FtsI-FtsL interaction.
      supported_by:
        - reference_id: PMID:18978050
          supporting_text: Characterization of YmgF, a 72-residue inner membrane
            protein that associates with the Escherichia coli cell division 
            machinery.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18978050
    review:
      summary: FtsI interacts with YmgF [PMID:18978050].
      action: ACCEPT
      reason: YmgF is a component of the E. coli cell division machinery.
      supported_by:
        - reference_id: PMID:18978050
          supporting_text: Characterization of YmgF, a 72-residue inner membrane
            protein that associates with the Escherichia coli cell division 
            machinery.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19458048
    review:
      summary: FtsI interacts with PBP1B. Crystal structure study of PBP1b 
        [PMID:19458048].
      action: ACCEPT
      reason: Supports FtsI-PBP1B interaction.
      supported_by:
        - reference_id: PMID:19458048
          supporting_text: Crystal structure of the membrane-bound bifunctional 
            transglycosylase PBP1b from Escherichia coli.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20847002
    review:
      summary: FtsI forms a subcomplex with FtsW. FRET and 
        co-immunoprecipitation experiments confirmed direct interactions 
        [PMID:20847002].
      action: ACCEPT
      reason: Key evidence for the FtsI-FtsW subcomplex. This is a core 
        interaction for divisome function.
      supported_by:
        - reference_id: PMID:20847002
          supporting_text: In this work we show direct interactions between FtsW
            and PBP3 in vivo and in vitro by FRET (FΓΆrster resonance energy 
            transfer) and co-immunoprecipitation experiments
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22885295
    review:
      summary: FtsI interacts with FtsL. Study on Blr protein and the division 
        machinery [PMID:22885295].
      action: ACCEPT
      reason: Additional evidence for FtsI-FtsL interaction.
      supported_by:
        - reference_id: PMID:22885295
          supporting_text: The Ξ²-lactam resistance protein Blr, a small membrane
            polypeptide, is a component of the Escherichia coli cell division 
            machinery.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24561554
    review:
      summary: FtsI interacts with MtgA. Large-scale binary protein-protein 
        interaction study [PMID:24561554].
      action: ACCEPT
      reason: High-throughput confirmation of FtsI-MtgA interaction.
      supported_by:
        - reference_id: PMID:24561554
          supporting_text: Here we performed yeast two-hybrid screens of 3,305 
            baits against 3,606 preys
  - term:
      id: GO:0000917
      label: division septum assembly
    evidence_type: NAS
    original_reference_id: PMID:28419603
    review:
      summary: FtsI is part of the divisome complex that assembles the division 
        septum. Review article [PMID:28419603].
      action: ACCEPT
      reason: Appropriate biological process annotation based on review 
        summarizing extensive experimental literature.
      supported_by:
        - reference_id: PMID:28419603
          supporting_text: Cell division in Escherichia coli is mediated by a 
            large protein complex called the divisome
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: NAS
    original_reference_id: PMID:28419603
    review:
      summary: FtsI localizes to the plasma membrane via its N-terminal 
        transmembrane anchor.
      action: ACCEPT
      reason: Correct localization annotation.
      supported_by:
        - reference_id: PMID:28419603
          supporting_text: Assembly and activation of the Escherichia coli 
            divisome.
  - term:
      id: GO:0032153
      label: cell division site
    evidence_type: NAS
    original_reference_id: PMID:28419603
    review:
      summary: FtsI localizes to the cell division site (septum) during cell 
        division.
      action: ACCEPT
      reason: Appropriate cellular component annotation supported by 
        experimental evidence [PMID:9603865].
      supported_by:
        - reference_id: PMID:9603865
          supporting_text: FtsI and FtsW are localized to the septum in 
            Escherichia coli
        - reference_id: PMID:28419603
          supporting_text: Assembly and activation of the Escherichia coli 
            divisome.
  - term:
      id: GO:0043093
      label: FtsZ-dependent cytokinesis
    evidence_type: NAS
    original_reference_id: PMID:28419603
    review:
      summary: FtsI functions in FtsZ-dependent cell division as part of the 
        divisome.
      action: ACCEPT
      reason: Appropriate biological process. FtsI localization depends on FtsZ.
      supported_by:
        - reference_id: PMID:9603865
          supporting_text: The localization of FtsI was not observed in ftsZ or 
            ftsA mutants
        - reference_id: PMID:28419603
          supporting_text: Assembly and activation of the Escherichia coli 
            divisome.
  - term:
      id: GO:0051301
      label: cell division
    evidence_type: NAS
    original_reference_id: PMID:28419603
    review:
      summary: FtsI is essential for cell division.
      action: ACCEPT
      reason: Core biological process for FtsI.
      supported_by:
        - reference_id: PMID:28419603
          supporting_text: Assembly and activation of the Escherichia coli 
            divisome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33895137
    review:
      summary: FtsI interacts with ZapG (YhcB, P0ADW3). ZapG is a novel cell 
        division protein linking the Z-ring to septal peptidoglycan synthesis 
        [PMID:33895137].
      action: ACCEPT
      reason: ZapG interacts with multiple divisome components including FtsI, 
        linking the Z-ring scaffold to peptidoglycan synthesis machinery.
      supported_by:
        - reference_id: PMID:33895137
          supporting_text: ZapG (YhcB/DUF1043), a novel cell division protein in
            gamma-proteobacteria linking the Z-ring to septal peptidoglycan 
            synthesis
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28233869
    review:
      summary: FtsI (PBP3) interacts with FtsW as part of a ternary complex with
        PBP1b [PMID:28233869]. The study characterized the interplay between 
        these proteins in peptidoglycan synthesis.
      action: ACCEPT
      reason: Key evidence showing FtsW-PBP3-PBP1b form a ternary complex 
        essential for divisome function.
      supported_by:
        - reference_id: PMID:28233869
          supporting_text: PBP3 forms a complex with FtsW and its specific 
            transpeptidase activity is essential for cell division
  - term:
      id: GO:0009252
      label: peptidoglycan biosynthetic process
    evidence_type: RCA
    original_reference_id: PMID:27525505
    review:
      summary: FtsI participates in peptidoglycan biosynthesis as the 
        transpeptidase that cross-links glycan strands during cell division 
        [PMID:27525505].
      action: ACCEPT
      reason: Core biological process. The SEDS paper confirms Class B PBPs like
        FtsI provide transpeptidase activity for cross-linking.
      supported_by:
        - reference_id: PMID:27525505
          supporting_text: cross-linking of adjacent glycan strands is likely 
            carried out by the essential Class B PBPs (for simplicity, bPBPs), 
            which have TP domains
  - term:
      id: GO:0008955
      label: peptidoglycan glycosyltransferase activity
    evidence_type: IMP
    original_reference_id: PMID:6450748
    review:
      summary: INCORRECT ANNOTATION. This 1981 paper predates the discovery that
        Class B PBPs lack glycosyltransferase activity. The glycosyltransferase 
        activity detected was likely due to contaminating Class A PBPs or the 
        associated SEDS protein FtsW. UniProt explicitly cautions this is an 
        error.
      action: REMOVE
      reason: 'Historical misattribution. Modern evidence [PMID:27525505] clearly
        shows Class B PBPs like FtsI lack glycosyltransferase activity. The SEDS protein
        FtsW (which forms a complex with FtsI) provides this activity. UniProt CAUTION
        states: "Was originally thought to be a bifunctional enzyme with transglycosylase
        and transpeptidase activities."'
      supported_by:
        - reference_id: PMID:27525505
          supporting_text: the essential Class B PBPs (for simplicity, bPBPs), 
            which have TP domains but lack PGT activity
        - reference_id: PMID:6450748
          supporting_text: Evidence for involvement of penicillin-binding 
            protein 3 in murein synthesis during septation but not during cell 
            elongation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20497333
    review:
      summary: FtsI interacts with FtsN. FRET study on divisome protein 
        interactions [PMID:20497333].
      action: ACCEPT
      reason: Evidence for FtsI-FtsN interaction.
      supported_by:
        - reference_id: PMID:20497333
          supporting_text: Epub 2010 May 19. Direct interactions of early and 
            late assembling division proteins in Escherichia coli cells resolved
            by FRET.
  - term:
      id: GO:0032153
      label: cell division site
    evidence_type: IDA
    original_reference_id: PMID:9603865
    review:
      summary: FtsI was shown to localize to the septum by immunofluorescence 
        microscopy [PMID:9603865].
      action: ACCEPT
      reason: Core cellular component annotation. Direct experimental evidence 
        (IDA) from immunofluorescence microscopy.
      supported_by:
        - reference_id: PMID:9603865
          supporting_text: The localization of FtsI (PBP3), a penicillin-binding
            protein specifically required for cell division in Escherichia coli,
            was investigated by immunofluorescence microscopy and found to 
            localize to the septum
  - term:
      id: GO:0008658
      label: penicillin binding
    evidence_type: IDA
    original_reference_id: PMID:1103132
    review:
      summary: Spratt 1975 demonstrated that beta-lactam antibiotics that 
        specifically inhibit cell division bind to PBP3 (FtsI) [PMID:1103132].
      action: ACCEPT
      reason: Core molecular function. Classic paper establishing FtsI as a 
        penicillin- binding protein with direct experimental evidence.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: 'Cell division: beta-Lactams that specifically inhibit
            cell division bind preferentially to penicillin binding protein 3 (molecular
            weight 60,000)'
  - term:
      id: GO:0009410
      label: response to xenobiotic stimulus
    evidence_type: IMP
    original_reference_id: PMID:1103132
    review:
      summary: FtsI binds beta-lactam antibiotics (xenobiotics), which inhibit 
        its activity and cause cell filamentation [PMID:1103132].
      action: KEEP_AS_NON_CORE
      reason: While accurate that FtsI responds to beta-lactam antibiotics 
        (xenobiotics), this is not a physiological function but rather a 
        pharmacological property. The response is inhibition of division. Keep 
        as non-core annotation.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: beta-Lactams that specifically inhibit cell division 
            bind preferentially to penicillin binding protein 3
  - term:
      id: GO:0051301
      label: cell division
    evidence_type: IMP
    original_reference_id: PMID:1103132
    review:
      summary: Temperature-sensitive FtsI mutants fail to divide at 
        non-permissive temperature, demonstrating FtsI is essential for cell 
        division [PMID:1103132].
      action: ACCEPT
      reason: Core biological process with strong IMP evidence. Spratt showed 
        that a temperature-sensitive cell division mutant has a thermolabile 
        protein 3.
      supported_by:
        - reference_id: PMID:1103132
          supporting_text: A temperature-sensitive cell division mutant has been
            shown to have a thermolabile protein 3
  - term:
      id: GO:0008955
      label: peptidoglycan glycosyltransferase activity
    evidence_type: IDA
    original_reference_id: PMID:7030331
    review:
      summary: INCORRECT ANNOTATION. This 1981 paper reported 
        glycosyltransferase activity for purified PBP3, but this was later shown
        to be incorrect. FtsI is a Class B PBP that lacks glycosyltransferase 
        activity. Any detected activity was likely from contaminating enzymes or
        the associated FtsW.
      action: REMOVE
      reason: Historical misattribution now known to be incorrect. Class B PBPs 
        lack glycosyltransferase (PGT) activity [PMID:27525505]. UniProt states 
        [PMID:7030331] in its CAUTION that FtsI was "originally thought to be a 
        bifunctional enzyme." The glycosyltransferase activity is provided by 
        SEDS proteins (FtsW) or Class A PBPs (PBP1a, PBP1b), not by FtsI.
      supported_by:
        - reference_id: PMID:27525505
          supporting_text: the essential Class B PBPs (for simplicity, bPBPs), 
            which have TP domains but lack PGT activity
        - reference_id: PMID:7030331
          supporting_text: 'Peptidoglycan synthetic enzyme activities of highly purified
            penicillin-binding protein 3 in Escherichia coli: a septum-forming reaction
            sequence.'
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000104
    title: Electronic Gene Ontology annotations created by transferring manual 
      GO annotations between related proteins based on shared sequence features
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:1103132
    title: Distinct penicillin binding proteins involved in the division, 
      elongation, and shape of Escherichia coli K12.
    findings: []
  - id: PMID:15774864
    title: Interaction network among Escherichia coli membrane proteins involved
      in cell division as revealed by bacterial two-hybrid analysis.
    findings: []
  - id: PMID:17185541
    title: Three functional subdomains of the Escherichia coli FtsQ protein are 
      involved in its interaction with the other division proteins.
    findings: []
  - id: PMID:17938168
    title: The essential cell division protein FtsN interacts with the murein 
      (peptidoglycan) synthase PBP1B in Escherichia coli.
    findings: []
  - id: PMID:18165305
    title: The monofunctional glycosyltransferase of Escherichia coli localizes 
      to the cell division site and interacts with penicillin-binding protein 3,
      FtsW, and FtsN.
    findings: []
  - id: PMID:18978050
    title: Characterization of YmgF, a 72-residue inner membrane protein that 
      associates with the Escherichia coli cell division machinery.
    findings: []
  - id: PMID:19458048
    title: Crystal structure of the membrane-bound bifunctional transglycosylase
      PBP1b from Escherichia coli.
    findings: []
  - id: PMID:20497333
    title: Direct interactions of early and late assembling division proteins in
      Escherichia coli cells resolved by FRET.
    findings: []
  - id: PMID:20847002
    title: The integral membrane FtsW protein and peptidoglycan synthase PBP3 
      form a subcomplex in Escherichia coli.
    findings: []
  - id: PMID:22885295
    title: The Ξ²-lactam resistance protein Blr, a small membrane polypeptide, is
      a component of the Escherichia coli cell division machinery.
    findings: []
  - id: PMID:24561554
    title: The binary protein-protein interaction landscape of Escherichia coli.
    findings: []
  - id: PMID:27525505
    title: SEDS proteins are a widespread family of bacterial cell wall 
      polymerases.
    findings: []
  - id: PMID:28233869
    title: Interplay between Penicillin-binding proteins and SEDS proteins 
      promotes bacterial cell wall synthesis.
    findings: []
  - id: PMID:28419603
    title: Assembly and activation of the Escherichia coli divisome.
    findings: []
  - id: PMID:33895137
    title: ZapG (YhcB/DUF1043), a novel cell division protein in 
      gamma-proteobacteria linking the Z-ring to septal peptidoglycan synthesis.
    findings: []
  - id: PMID:6450748
    title: Evidence for involvement of penicillin-binding protein 3 in murein 
      synthesis during septation but not during cell elongation.
    findings: []
  - id: PMID:7030331
    title: 'Peptidoglycan synthetic enzyme activities of highly purified penicillin-binding
      protein 3 in Escherichia coli: a septum-forming reaction sequence.'
    findings: []
  - id: PMID:9603865
    title: FtsI and FtsW are localized to the septum in Escherichia coli.
    findings: []
  - id: PMID:2677607
    title: Membrane topology of penicillin-binding protein 3 of Escherichia 
      coli.
    findings: []
  - id: PMID:9282742
    title: FtsN, a late recruit to the septum in Escherichia coli.
    findings: []
  - id: PMID:9614966
    title: The structure and function of Escherichia coli penicillin-binding 
      protein 3.
    findings: []
  - id: PMID:3531167
    title: Activity of penicillin-binding protein 3 from Escherichia coli.
    findings: []
  - id: file:ECOLI/ftsI/ftsI-deep-research-falcon.md
    title: Deep research on ftsI function
    findings: []
core_functions:
  - molecular_function:
      id: GO:0009002
      label: serine-type D-Ala-D-Ala carboxypeptidase activity
    description: 'Septal peptidoglycan cross-linking: FtsI catalyzes the transpeptidation
      reaction that cross-links peptidoglycan strands specifically at the division
      septum. It is a D,D-transpeptidase (EC 3.4.16.4) that cleaves D-Ala-D-Ala bonds
      and forms peptide cross-links. This is the primary enzymatic activity of FtsI
      [PMID:3531167, PMID:7030331].'
  - molecular_function:
      id: GO:0008658
      label: penicillin binding
    description: 'Penicillin binding: FtsI is one of the major penicillin-binding
      proteins (PBP3). Beta-lactam antibiotics inhibit FtsI by binding to its active
      site serine, blocking cell division [PMID:1103132]. This property makes FtsI
      a key antibiotic target.'
aliases:
  - PBP3
  - PbpB
  - b0084
  - JW0082