Endogenous protein lipoylation

Endogenous protein lipoylation builds a lipoyl cofactor directly on conserved lysine residues in lipoyl domains. All characterized routes transfer an octanoyl group from octanoyl-acyl carrier protein to a protein carrier and use a radical-SAM lipoate synthase to insert sulfur atoms at C6 and C8. In the modeled routes, the topology varies by lineage: some organisms modify client lipoyl domains directly, whereas others use GcvH as an obligatory relay carrier and an amidotransferase to deliver the modified acyl group to client proteins. This module models the direct bacterial route, the characterized Bacillus relay, and the characterized human mitochondrial relay as alternatives. Exogenous lipoate salvage by ATP-dependent lipoate-protein ligases and the downstream lipoate-dependent enzyme complexes are outside the boundary.

MODULE:endogenous_protein_lipoylationDRAFTMetabolic Pathwaymodules/endogenous_protein_lipoylation.yaml
protein lipoylationGO:0009249
GO:0009249
protein lipoylation
The module represents the endogenous reactions that covalently install a lipoyl cofactor on protein lipoyl domains.
file:modules/endogenous_protein_lipoylation-deep-research-openscientist.md
OpenScientist review of endogenous protein lipoylation
The review supports a conserved octanoyl-transfer and sulfur-insertion chemistry with direct and GcvH-relay topological variants.
file:projects/P_PUTIDA/deep-research/PSEPK__endogenous_protein_lipoylation__ppu00785-deep-research-openscientist.md
OpenScientist review of endogenous protein lipoylation in Pseudomonas putida KT2440
The taxon review supports LipB Q88DM4 and LipA Q88DM5 as the complete direct route in KT2440 and flags PP_0423 as an uncertain LipM/LipL-family candidate outside the KEGG pathway bucket.
file:interpro/panther/PTHR10993/PTHR10993-paint.tsv
PAINT assertions for LipB-family octanoyltransferases
PTN000107427 carries an IBD assertion for GO:0033819 seeded by reviewed Escherichia coli LipB P60720 and Mycobacterium tuberculosis P9WK83.
file:interpro/panther/PTHR10949/PTHR10949-paint.tsv
PAINT assertions for eukaryotic lipoyl synthases
PTN000101947 carries an IBD assertion for GO:0016992 seeded in part by reviewed human LIAS O43766.
12Nodes
8Parts
1Variant Sets
3Variants
8Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • endogenous_protein_lipoylation-deep-research-openscientist.md (openscientist)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

5 gene-function check(s) reflected in core functions · 0 conflict(s) · 13 evidence or coverage gap(s) (18 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
direct_lipb_activity LipB (Pseudomonas putida KT2440)
UniProtKB:Q88DM4
Family Representative 		lipoyl(octanoyl) transferase activity
GO:0033819 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
direct_lipb_activity LipB (Escherichia coli K-12)
UniProtKB:P60720
Family Representative 		lipoyl(octanoyl) transferase activity
GO:0033819 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
direct_lipa_activity LipA (Pseudomonas putida KT2440)
UniProtKB:Q88DM5
Family Representative 		lipoate synthase activity
GO:0016992 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
direct_lipa_activity LipA (Escherichia coli K-12)
UniProtKB:P60716
Family Representative 		lipoate synthase activity
GO:0016992 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bacillus_lipm_activity LipM (Bacillus subtilis 168)
UniProtKB:P54511
Family Representative 		GcvH-directed lipoyl(octanoyl) transferase activity
GO:0033819 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bacillus_lipl_activity LipL (Bacillus subtilis 168)
UniProtKB:P39648
Family Representative 		octanoyl-GcvH:protein amidotransferase activity
No function ID 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. The module function also lacks a GO identifier.
bacillus_lipa_activity LipA (Bacillus subtilis 168)
UniProtKB:O32129
Family Representative 		lipoate synthase activity
GO:0016992 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_lipt2_activity LIPT2 (human)
UniProtKB:A6NK58
Family Representative 		GCSH-directed lipoyl(octanoyl) transferase activity
GO:0033819 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
human_lias_activity LIAS (human)
UniProtKB:O43766
Family Representative 		lipoate synthase activity
GO:0016992 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
human_lipt1_activity LIPT1 (human)
UniProtKB:Q9Y234
Family Representative 		lipoyl-GCSH:protein amidotransferase activity
No function ID 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked. The module function also lacks a GO identifier.
direct_lipb_activity LipB family octanoyltransferases
PANTHER:PTHR10993
Family 		lipoyl(octanoyl) transferase activity
GO:0033819 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10993.
direct_lipa_activity LipA family lipoate synthases
PANTHER:PTHR10949
Family 		lipoate synthase activity
GO:0016992 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10949.
bacillus_lipm_activity Octanoyltransferase LipM family
InterPro:IPR024898
Family 		GcvH-directed lipoyl(octanoyl) transferase activity
GO:0033819 		Family Review Missing
No supported structured family review is available for InterPro:IPR024898.
bacillus_lipl_activity Octanoyltransferase LipL family
InterPro:IPR024897
Family 		octanoyl-GcvH:protein amidotransferase activity
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.
bacillus_lipa_activity LipA family lipoate synthases
PANTHER:PTHR10949
Family 		lipoate synthase activity
GO:0016992 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10949.
human_lipt2_activity LipB family octanoyltransferases
PANTHER:PTHR10993
Family 		GCSH-directed lipoyl(octanoyl) transferase activity
GO:0033819 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10993.
human_lias_activity LipA family lipoate synthases
PANTHER:PTHR10949
Family 		lipoate synthase activity
GO:0016992 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10949.
human_lipt1_activity LIPT1 lipoyl amidotransferase subfamily
PANTHER:PTHR12561:SF3
Family 		lipoyl-GCSH:protein amidotransferase activity
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.

Gene-review completeness (5/10 grounded genes reviewed)

5 complete review(s) · 4 with deep research · 5 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
LIPT2 (human) A6NK58 ✗ — —
LIAS O43766 ✓ ✓ ✓
lipA O32129 ✓ ✓ ✓
lipA P60716 ✓ ✓ ✗
lipA Q88DM5 ✓ ✓ ✓
lipB Q88DM4 ✓ ✓ ✓
LipL (Bacillus subtilis 168) P39648 ✗ — —
LipM (Bacillus subtilis 168) P54511 ✗ — —
LipB (Escherichia coli K-12) P60720 ✗ — —
LIPT1 (human) Q9Y234 ✗ — —

Details

Endogenous protein lipoylationMetabolic Pathwayendogenous_protein_lipoylation
protein lipoylationGO:0009249

These variants are separately characterized implementations of conserved endogenous lipoylation chemistry, not universal taxonomic rules. The ONE_OR_MORE selection deliberately avoids asserting strict exclusivity but does not claim coexistence. Molecular functions occur only on leaf annotons, no generic module-level location is asserted, and salvage ligases plus downstream client complexes remain outside the boundary.

Variant set: Endogenous protein-lipoylation topologies by route topology and lineage (One Or More)

The variants preserve the same chemistry but differ in whether the octanoyl or lipoyl group is relayed through GcvH before reaching client E2 lipoyl domains. ONE_OR_MORE is relaxed modeling, not evidence that the routes coexist in one organism. The cited work generally describes lineage-associated alternatives; coexistence and strict exclusivity remain untested and must be assessed for each concrete realization.

Direct LipB-LipA routeMetabolic Pathwaydirect_lipb_lipa_route

LipB transfers octanoyl from octanoyl-ACP directly to a client lipoyl domain, and LipA inserts both sulfur atoms on that protein-bound intermediate. This is the characterized route in Escherichia coli; other organisms require independent evidence for this topology.

Connections

Direct LipB octanoylation precedes LipA sulfur insertion.
Part 1: direct octanoyl transfer from acyl carrier protein to a client lipoyl domain
Direct octanoylation of a client lipoyl domainReactiondirect_lipb_octanoyl_transfer

Annotons

LipB-family octanoyltransferase
direct_lipb_activity
Participant: Family: LipB family octanoyltransferases
Family:
LipB family octanoyltransferasesPANTHER:PTHR10993
Representative Members: LipB (Pseudomonas putida KT2440)UniProtKB:Q88DM4 LipB (Escherichia coli K-12)UniProtKB:P60720

Function

lipoyl(octanoyl) transferase activityGO:0033819
Substrates: octanoyl-[acyl-carrier protein] apo client lipoyl-domain protein
Products: acyl-carrier protein octanoylated client lipoyl-domain protein

Produces the protein-bound octanoyl intermediate used by LipA.

Part 2: sulfur insertion into the directly octanoylated client lipoyl domain
Sulfur insertion on the client lipoyl domainReactiondirect_lipa_sulfur_insertion

Annotons

LipA-family lipoate synthase
direct_lipa_activity
Participant: Family: LipA family lipoate synthases
Family:
LipA family lipoate synthasesPANTHER:PTHR10949
Representative Members: LipA (Pseudomonas putida KT2440)UniProtKB:Q88DM5 LipA (Escherichia coli K-12)UniProtKB:P60716

Function

lipoate synthase activityGO:0016992
Substrates: octanoylated client lipoyl-domain protein S-adenosyl-L-methionine
Products: lipoylated client protein 5'-deoxyadenosine L-methionine

Completes lipoyl-cofactor formation on the client protein.

Bacillus GcvH octanoyl-relay routeMetabolic Pathwaybacillus_gcvh_octanoyl_relay_route

In the characterized Bacillus subtilis route, LipM octanoylates GcvH, LipL transfers octanoyl from GcvH to client E2 lipoyl domains, and LipA inserts sulfur on the client-bound intermediate. This variant is not a generic claim about the order in every GcvH-relay lineage.

Connections

GcvH carries octanoyl from LipM to LipL.
LipL transfer to E2 precedes LipA sulfur insertion.
Part 1: octanoyl transfer from acyl carrier protein to GcvH
LipM-dependent GcvH octanoylationReactionbacillus_lipm_gcvh_octanoylation

Annotons

LipM octanoyltransferase
bacillus_lipm_activity
Participant: Family: Octanoyltransferase LipM family
Family:
Octanoyltransferase LipM familyInterPro:IPR024898
Representative Members: LipM (Bacillus subtilis 168)UniProtKB:P54511

Function

GcvH-directed lipoyl(octanoyl) transferase activityGO:0033819
Substrates: octanoyl-[acyl-carrier protein] apo-GcvH
Products: acyl-carrier protein octanoyl-GcvH

Loads the octanoyl group onto the obligatory GcvH relay carrier.

Part 2: transfer of octanoyl from GcvH to client E2 lipoyl domains
LipL-dependent octanoyl relay to E2Reactionbacillus_lipl_octanoyl_relay

Annotons

LipL octanoyl-GcvH amidotransferase
bacillus_lipl_activity
Participant: Family: Octanoyltransferase LipL family
Family:
Octanoyltransferase LipL familyInterPro:IPR024897
Representative Members: LipL (Bacillus subtilis 168)UniProtKB:P39648

Function

octanoyl-GcvH:protein amidotransferase activity Transfers octanoyl from the lipoyl lysine of GcvH to a client E2 lipoyl-domain lysine. No precise GO term was identified for this octanoyl-GcvH donor reaction, so the function remains grounded by exact RHEA:20213 rather than the uninformative acyltransferase parent.
Substrates: octanoyl-GcvH apo E2 lipoyl-domain protein
Products: apo-GcvH octanoylated E2 lipoyl-domain protein

Relays the octanoyl group from GcvH to the client E2 lipoyl domain.

Part 3: sulfur insertion into octanoylated client E2 lipoyl domains
LipA sulfur insertion on client E2Reactionbacillus_lipa_sulfur_insertion

Annotons

Bacillus LipA lipoate synthase
bacillus_lipa_activity
Participant: Family: LipA family lipoate synthases
Family:
LipA family lipoate synthasesPANTHER:PTHR10949
Representative Members: LipA (Bacillus subtilis 168)UniProtKB:O32129

Function

lipoate synthase activityGO:0016992
Substrates: octanoylated E2 lipoyl-domain protein S-adenosyl-L-methionine
Products: lipoylated E2 protein 5'-deoxyadenosine L-methionine

Converts the relayed octanoyl group on the client E2 protein to mature lipoyllysine.

Human mitochondrial GCSH lipoyl-relay routeMetabolic Pathwayhuman_gcvh_lipoyl_relay_route

In human mitochondria, LIPT2 transfers octanoyl from mitochondrial acyl carrier protein to GCSH, LIAS inserts sulfur on GCSH-bound octanoyl, and LIPT1 transfers the mature lipoyl group from GCSH to client E2 lipoyl domains.

Connections

GCSH-bound octanoyl is sulfurated before transfer to E2.
Mature lipoyl is relayed from GCSH to client E2 proteins.
Part 1: octanoyl transfer from mitochondrial acyl carrier protein to GCSH
LIPT2-dependent GCSH octanoylationReactionhuman_lipt2_gcsh_octanoylation

Annotons

LIPT2 octanoyltransferase
human_lipt2_activity
Participant: Family: LipB family octanoyltransferases
Family:
LipB family octanoyltransferasesPANTHER:PTHR10993
Representative Members: LIPT2 (human)UniProtKB:A6NK58

Function

GCSH-directed lipoyl(octanoyl) transferase activityGO:0033819
Substrates: octanoyl-[mitochondrial acyl-carrier protein] apo-GCSH
Products: mitochondrial acyl-carrier protein octanoyl-GCSH

Loads octanoyl onto the mitochondrial GCSH relay carrier.

Part 2: sulfur insertion into GCSH-bound octanoyl
LIAS sulfur insertion on GCSHReactionhuman_lias_gcsh_sulfur_insertion

Annotons

LIAS lipoate synthase
human_lias_activity
Participant: Family: LipA family lipoate synthases
Family:
LipA family lipoate synthasesPANTHER:PTHR10949
Representative Members: LIAS (human)UniProtKB:O43766

Function

lipoate synthase activityGO:0016992
Substrates: octanoyl-GCSH S-adenosyl-L-methionine
Products: lipoyl-GCSH 5'-deoxyadenosine L-methionine

Builds mature lipoyllysine on the GCSH relay carrier.

Part 3: transfer of mature lipoyl from GCSH to client E2 lipoyl domains
LIPT1-dependent lipoyl relay to E2Reactionhuman_lipt1_lipoyl_relay

Annotons

LIPT1 lipoyl-GCSH amidotransferase
human_lipt1_activity
Participant: Family: LIPT1 lipoyl amidotransferase subfamily
Family:
LIPT1 lipoyl amidotransferase subfamilyPANTHER:PTHR12561:SF3
Representative Members: LIPT1 (human)UniProtKB:Q9Y234

Function

lipoyl-GCSH:protein amidotransferase activity Transfers mature lipoyl from GCSH to a client E2 lipoyl-domain lysine. Exact RHEA:16413 distinguishes this physiological relay from ATP-dependent free-lipoate ligation; the uninformative acyltransferase parent is omitted.
Substrates: lipoyl-GCSH apo E2 lipoyl-domain protein
Products: apo-GCSH lipoylated E2 protein

Delivers mature lipoyl from GCSH to the mitochondrial 2-oxoacid dehydrogenase E2 subunits.