De novo biotin biosynthesis (pimelate-thioester supply and BioF-BioA-BioD-BioB ring assembly)

De novo synthesis of biotin in bacteria, fungi and plants. A seven-carbon pimelate thioester (pimeloyl-ACP or pimeloyl-CoA) is first made by a lineage-specific route, and four conserved reactions then assemble the two rings of biotin. In many bacteria, BioC methylates malonyl-ACP, the shared fatty-acid-synthase reactions extend the masked intermediate to pimeloyl-ACP methyl ester, and BioH removes the methyl group. Filamentous fungi make pimeloyl-CoA by peroxisomal beta-oxidation, and Saccharomyces yeasts need the oxygen-dependent BIO1 protein, whose reaction is not known. The pimelate thioester is condensed with L-alanine to 8-amino-7-oxononanoate (KAPA) by a PLP-dependent KAPA synthase: bacterial BioF, a peroxisomal BioF in filamentous fungi, or, in Saccharomyces, a step that requires the BIO6 protein, a paralogue of the BioA aminotransferase. BioA then transfers an amino group from S-adenosylmethionine to give 7,8-diaminononanoate (DAPA), BioD closes the ureido ring with CO2 and ATP to give dethiobiotin, and the radical-SAM enzyme BioB inserts sulfur to form biotin. In fungi BioB is mitochondrial, and in filamentous fungi and plants BioD and BioA are fused in one protein. Biotin attachment to carboxylases, biotin uptake and regulation are outside the module.

MODULE:biotin_biosynthesisDRAFTMetabolic Pathwaymodules/biotin_biosynthesis.yaml
biotin biosynthetic processGO:0009102
YeastPathways:BIOTIN-SYNTHESIS-PWY
biotin biosynthesis (S. cerevisiae, SGD YeastPathways)
Source pathway for the Saccharomyces variant. It lists BIO3 (DAPA aminotransferase), BIO4 (dethiobiotin synthetase) and BIO2 (biotin synthase), all placed in cytosol, and leaves the KAPA synthase reaction (7KAPSYN-RXN) without a gene because the reference strain S288C lacks BIO1 and BIO6. This module adds BIO1 (pimelate-thioester supply) and BIO6 (KAPA formation) from biotin-prototrophic strains and places BIO2 in the mitochondrion.
KEGG:ppu00780
Pseudomonas putida KT2440 biotin metabolism
The PSEPK pathway bucket contains the bioBFHCD cluster and the separate bioA gene, together with generic fatty-acid and biotin-utilization genes that require boundary curation.
GO:0009102
biotin biosynthetic process
The module is grounded in the GO biological-process term for biotin synthesis.
PMID:10333520
Characterization of the biotin biosynthesis pathway in Saccharomyces cerevisiae and evidence for a cluster containing BIO5, a novel gene involved in vitamer uptake.
BIO3 and BIO4 encode DAPA aminotransferase and dethiobiotin synthase; BIO5 encodes a KAPA uptake protein.
We demonstrate that BIO3 (YNR058w) and BIO4 (YNR057c) encode, respectively, a 7, 8-diaminopelargonic acid aminotransferase and a dethiobiotin synthase, involved in the biotin biosynthesis pathway.
PMID:8117110
The gene for biotin synthase from Saccharomyces cerevisiae: cloning, sequencing, and complementation of Escherichia coli strains lacking biotin synthase.
BIO2 encodes yeast biotin synthase.
PMID:16269718
Identification and characterization of a novel biotin biosynthesis gene in Saccharomyces cerevisiae.
BIO6, a BIO3 homologue present in sake and some laboratory strains, is required for biotin prototrophy and acts before KAPA.
These results suggest that Bio6p acts in an unknown step of biotin synthesis before KAPA synthesis.
PMID:18073433
The reacquisition of biotin prototrophy in Saccharomyces cerevisiae involved horizontal gene transfer, gene duplication and gene clustering.
BIO1 and BIO6 together restore biotin prototrophy to S288C; BIO1 is a paralogue of YJR154W, and the pathway was rebuilt in the Saccharomyces lineage by horizontal transfer and gene duplication.
The biotin auxotroph strain S288c was able to grow on media lacking biotin when BIO1 and the known biotin synthesis gene BIO6 were introduced together on a plasmid vector.
PMID:32276977
Exploiting the Diversity of Saccharomycotina Yeasts To Engineer Biotin-Independent Growth of Saccharomyces cerevisiae.
Bio1 is the bottleneck of yeast biotin synthesis, its catalytic function is unresolved, and biotin prototrophy conferred by Bio1 needs oxygen.
identified Bio1, whose catalytic function remains unresolved, as a bottleneck in biotin synthesis
PMID:34052444
Engineering oxygen-independent biotin biosynthesis in Saccharomyces cerevisiae.
De novo biotin synthesis in S. cerevisiae needs oxygen; expression of the E. coli pimelate-thioester route makes it oxygen-independent.
PMID:21998305
Contributions of the peroxisome and β-oxidation cycle to biotin synthesis in fungi.
Fungal KAPA (AON) synthase is peroxisomal and uses pimeloyl-CoA from peroxisomal beta-oxidation; Saccharomyces species lack this enzyme and use a different route for the pimelate intermediate.
AON synthases with PTS1 are found throughout the fungal kingdom, in ascomycetes, basidiomycetes, and members of basal fungal lineages but not in representatives of the Saccharomyces species complex, including Saccharomyces cerevisiae.
PMID:20713166
Characterization of the Aspergillus nidulans biotin biosynthetic gene cluster and use of the bioDA gene as a new transformation marker.
In A. nidulans and many filamentous fungi, basidiomycetes and plants, DAPA aminotransferase and dethiobiotin synthetase are one bifunctional BioDA protein.
file:projects/P_PUTIDA/deep-research/PSEPK__biotin_biosynthesis__ppu00780-deep-research-openscientist.md
OpenScientist module/pathway/taxon report for PSEPK biotin biosynthesis
Supports coverage of all six pathway-specific reactions, exclusion of BirA and generic fatty-acid-synthesis proteins from dedicated membership, and complete pathway satisfiability in KT2440. Individual enzyme assignments remain homology- and genomic-context-based rather than direct KT2440 biochemical evidence.
file:modules/biotin_biosynthesis-deep-research-openscientist.md
OpenScientist research for the reusable BioC-BioH biotin pathway
The generic synthesis supports a six-enzyme BioC-BioH de novo route, with shared fatty-acid elongation between BioC and BioH treated as a dependency rather than dedicated pathway membership.
file:projects/P_PUTIDA/data/psepk_pathway_membership.tsv
PSEPK pathway membership table
Supplies exact locus, gene-symbol, accession, and pathway-bucket mappings used for the PSEPK satisfiability pass.
UniProtKB:P12999
Reviewed Escherichia coli BioC malonyl-ACP O-methyltransferase
P12999 is an experimentally characterized cross-species exemplar for malonyl-ACP methylation and the modified-fatty-acid-synthesis route.
UniProtKB:P13001
Reviewed Escherichia coli BioH pimeloyl-ACP methyl ester esterase
P13001 is an experimentally characterized cross-species exemplar for pathway-specific hydrolysis of pimeloyl-ACP methyl ester.
UniProtKB:P12998
Reviewed Escherichia coli BioF 8-amino-7-oxononanoate synthase
P12998 is an experimentally characterized cross-species exemplar for the pimeloyl-ACP and L-alanine condensation reaction.
UniProtKB:P12995
Reviewed Escherichia coli BioA aminotransferase
P12995 is an experimentally characterized cross-species exemplar for SAM-dependent 7,8-diaminononanoate formation.
UniProtKB:P13000
Reviewed Escherichia coli BioD dethiobiotin synthetase
P13000 is an experimentally characterized cross-species exemplar for ATP-dependent dethiobiotin ring closure.
UniProtKB:P12996
Reviewed Escherichia coli BioB biotin synthase
P12996 is an experimentally characterized cross-species exemplar for the terminal radical-SAM sulfur-insertion reaction.
UniProtKB:P32451
Reviewed S. cerevisiae BIO2 biotin synthase, mitochondrial
UniProt records a mitochondrial location for BIO2 with experimental evidence (ECO:0000269, PMID:14562095).
file:interpro/panther/PTHR13693/PTHR13693-paint.tsv
PAINT assertions for the BioF family
PTN000343971 carries IBD assertions for GO:0008710 and GO:0009102, seeded in part by experimentally characterized E. coli P12998.
file:interpro/panther/PTHR42684/PTHR42684-paint.tsv
PAINT assertions for the BioA family
PTN000241343 carries IBD assertions for GO:0004015 and GO:0009102, seeded by E. coli P12995, S. cerevisiae BIO3 (SGD:S000005341) and others.
file:interpro/panther/PTHR43210/PTHR43210-paint.tsv
PAINT assertions for the BioD family
PTN000482092 carries an IBD assertion for GO:0004141, seeded by E. coli P13000 and S. cerevisiae BIO4 (SGD:S000005340) among others.
file:interpro/panther/PTHR22976/PTHR22976-paint.tsv
PAINT assertions for the BioB family
PTN000540961 carries IBD assertions for GO:0004076 and GO:0009102, seeded by E. coli P12996, S. cerevisiae BIO2 (SGD:S000003518) and S. pombe bio2 (PomBase:SPCC1235.02).
14Nodes
7Parts
2Variant Sets
6Variants
9Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

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

Leaf nodes lacking representative members

1 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • bioC_step → bioH_step [NOT_CHECKED]
    Shared fatty-acid-synthase reactions perform two elongation cycles between the BioC and BioH pathway-specific control points.
  • bioF_step → bioA_step [NOT_CHECKED]
  • bioA_step → bioD_step [NOT_CHECKED]
  • bioD_step → bioB_step [NOT_CHECKED]

Function consistency and core coverage

12 gene-function check(s) reflected in core functions · 0 conflict(s) · 15 evidence or coverage gap(s) (30 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
bioC_activity bioC (Pseudomonas putida KT2440)
UniProtKB:Q88QW9
Family Representative 		malonyl-ACP O-methyltransferase activity
GO:0102130 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioC_activity bioC (Escherichia coli K-12)
UniProtKB:P12999
Family Representative 		malonyl-ACP O-methyltransferase activity
GO:0102130 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bioH_activity bioH (Pseudomonas putida KT2440)
UniProtKB:Q88QX0
Family Representative 		pimeloyl-ACP methyl ester esterase activity
GO:0090499 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioH_activity bioH (Escherichia coli K-12)
UniProtKB:P13001
Family Representative 		pimeloyl-ACP methyl ester esterase activity
GO:0090499 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bio1_pimelate_supply_activity BIO1 (Saccharomyces cerevisiae A364a)
UniProtKB:E9P9F6
Family Representative 		pimelate-thioester supply (catalytic activity unknown)
No function ID 		No Function Id
A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
bioF_activity bioF (Pseudomonas putida KT2440)
UniProtKB:Q88QX1
Family Representative 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioF_activity bioF (Escherichia coli K-12)
UniProtKB:P12998
Family Representative 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fungal_biof_activity bioF (Aspergillus nidulans)
UniProtKB:C8V1D1
Family Representative 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bio6_kapa_formation_activity BIO6 (Saccharomyces cerevisiae A364a)
UniProtKB:E9P8E0
Family Representative 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Function Unreviewed
No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
bioA_activity bioA (Pseudomonas putida KT2440)
UniProtKB:Q88D44
Family Representative 		adenosylmethionine-8-amino-7-oxononanoate transaminase activity
GO:0004015 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioA_activity bioA (Escherichia coli K-12)
UniProtKB:P12995
Family Representative 		adenosylmethionine-8-amino-7-oxononanoate transaminase activity
GO:0004015 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bioA_activity BIO3 (Saccharomyces cerevisiae)
UniProtKB:P50277
Family Representative 		adenosylmethionine-8-amino-7-oxononanoate transaminase activity
GO:0004015 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioA_activity bioDA (Aspergillus nidulans)
UniProtKB:Q5AYI6
Family Representative 		adenosylmethionine-8-amino-7-oxononanoate transaminase activity
GO:0004015 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bioD_activity bioD (Pseudomonas putida KT2440)
UniProtKB:Q88QW8
Family Representative 		dethiobiotin synthase activity
GO:0004141 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioD_activity bioD (Escherichia coli K-12)
UniProtKB:P13000
Family Representative 		dethiobiotin synthase activity
GO:0004141 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bioD_activity BIO4 (Saccharomyces cerevisiae)
UniProtKB:P53630
Family Representative 		dethiobiotin synthase activity
GO:0004141 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioB_activity bioB (Pseudomonas putida KT2440)
UniProtKB:Q88QX2
Family Representative 		biotin synthase activity
GO:0004076 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioB_activity bioB (Escherichia coli K-12)
UniProtKB:P12996
Family Representative 		biotin synthase activity
GO:0004076 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioB_activity BIO2 (Saccharomyces cerevisiae)
UniProtKB:P32451
Family Representative 		biotin synthase activity
GO:0004076 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioB_activity bio2 (Schizosaccharomyces pombe)
UniProtKB:O59778
Family Representative 		biotin synthase activity
GO:0004076 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bioB_activity bioB (Aspergillus nidulans)
UniProtKB:Q5AYI7
Family Representative 		biotin synthase activity
GO:0004076 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bioC_activity BioC malonyl-ACP O-methyltransferase family
NCBIfam:TIGR02072
Family 		malonyl-ACP O-methyltransferase activity
GO:0102130 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR02072.
bioH_activity BioH pimeloyl-ACP methyl ester esterase family
PANTHER:PTHR43194:SF5
Family 		pimeloyl-ACP methyl ester esterase activity
GO:0090499 		Family Supported
Family review supports GO:0090499 for PANTHER:PTHR43194:SF5. BioH activity holds for the BioH orthologs in SF5, but not for the PhaG/RhlA acyltransferases that share SF5.
bio1_pimelate_supply_activity Saccharomyces BIO1 (PhyH family)
PANTHER:PTHR21308
Family 		pimelate-thioester supply (catalytic activity unknown)
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.
bioF_activity proteobacterial BioF family
PANTHER:PTHR13693:SF100
Family 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Family Function Unreviewed
Family review leaves GO:0008710 UNRESOLVED. BioF lies in at least three subfamilies, and each also holds non-BioF members. SF100 holds CqsA. SF77 holds the sphA sphingofungin enzymes. SF3 holds eukaryotic SPT, bacterial SPT, KBL and secondary-metabolism enzymes. A few BioF are unassigned to any subfamily. The term is safe only by PAINT node or by member. The biotin_biosynthesis module's SF100 and SF77 selectors each also select non-BioF proteins (CqsA and sphA respectively), and they miss the Bacillus BioF of SF3.
fungal_biof_activity fungal PTS1-bearing BioF subfamily
PANTHER:PTHR13693:SF77
Family 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Family Function Unreviewed
Family review leaves GO:0008710 UNRESOLVED. BioF lies in at least three subfamilies, and each also holds non-BioF members. SF100 holds CqsA. SF77 holds the sphA sphingofungin enzymes. SF3 holds eukaryotic SPT, bacterial SPT, KBL and secondary-metabolism enzymes. A few BioF are unassigned to any subfamily. The term is safe only by PAINT node or by member. The biotin_biosynthesis module's SF100 and SF77 selectors each also select non-BioF proteins (CqsA and sphA respectively), and they miss the Bacillus BioF of SF3.
bio6_kapa_formation_activity Saccharomyces BIO6 (BioA-like class-III aminotransferase)
PANTHER:PTHR42684
Family 		8-amino-7-oxononanoate synthase activity
GO:0008710 		Family Function Unreviewed
Family review leaves GO:0008710 UNRESOLVED. Asserted by the biotin_biosynthesis module (and by SGD as ISS) for Saccharomyces BIO6 only. Genetics place BIO6 before KAPA, but no activity of purified BIO6 has been reported. KAPA synthase is otherwise a class II alpha-oxoamine synthase reaction (BioF, PTHR13693), and BIO6 is a class III aminotransferase-fold BIO3 paralog. The BIO6 review leaves the ISS UNDECIDED. The term is not safe for any other member of this family.
bioA_activity BioA aminotransferase family
PANTHER:PTHR42684
Family 		adenosylmethionine-8-amino-7-oxononanoate transaminase activity
GO:0004015 		Family Function Unreviewed
Family review leaves GO:0004015 UNRESOLVED. Holds for bacterial BioA (SF17) and for the eukaryotic and cyanobacterial BioA members of SF3 (BIO3, the BioDA fusions, Synechococcus BioA). SF3 also contains the pyruvate-dependent GABA transaminases. SF17 contains BIO6, whose activity is unknown and which acts before KAPA. Neither subfamily is therefore safe as a whole. The biotin_biosynthesis BioA annoton uses the family id PTHR42684, which also selects every GABA transaminase, vanillin aminotransferase and BauA. A required_function or member-level selector is needed.
bioD_activity BioD dethiobiotin synthase family
PANTHER:PTHR43210:SF5
Family 		dethiobiotin synthase activity
GO:0004141 		Family Supported
Family review supports GO:0004141 FAMILY_WIDE. The single activity of the family, across SF5, SF2 and SF4. The biotin_biosynthesis module selects only SF5. That covers its exemplars (E. coli BioD1, P. putida BioD, BIO4) but leaves out the BioD of SF2 (for example B. subtilis) and SF4 (enterobacterial BioD2). The family-level id PTHR43210 would be the complete selector.
bioB_activity BioB radical-SAM biotin synthase family
PANTHER:PTHR22976
Family 		biotin synthase activity
GO:0004076 		Family Supported
Family review supports GO:0004076 FAMILY_WIDE. The family's activity, safe for SF2 as a whole except for the archaeal radical-SAM paralogs listed as member exceptions. The biotin_biosynthesis module selects the whole family.

Gene-review completeness (14/21 grounded genes reviewed)

10 complete review(s) · 10 with deep research · 7 missing review · 4 reviewed but lacking deep research

Gene Review Complete Deep research
BIO1 E9P9F6 ✓ 6/7 ✓
bio2 O59778 ✓ ✓ ✗
BIO2 P32451 ✓ ✓ ✓
BIO3 P50277 ✓ 12/13 ✓
BIO4 P53630 ✓ 11/12 ✓
BIO6 E9P8E0 ✓ 6/7 ✓
bioA Q88D44 ✓ ✓ ✗
bioB P12996 ✓ ✓ ✗
bioB Q88QX2 ✓ ✓ ✓
bioC Q88QW9 ✓ ✓ ✓
bioD Q88QW8 ✓ ✓ ✓
bioF P12998 ✓ ✓ ✗
bioF Q88QX1 ✓ ✓ ✓
bioH Q88QX0 ✓ ✓ ✓
bioF (Aspergillus nidulans) C8V1D1 ✗ — —
bioA (Escherichia coli K-12) P12995 ✗ — —
bioC (Escherichia coli K-12) P12999 ✗ — —
bioD (Escherichia coli K-12) P13000 ✗ — —
bioH (Escherichia coli K-12) P13001 ✗ — —
bioDA (Aspergillus nidulans) Q5AYI6 ✗ — —
bioB (Aspergillus nidulans) Q5AYI7 ✗ — —

Details

de novo biotin biosynthesisMetabolic Pathwaybiotin_biosynthesis
biotin biosynthetic processGO:0009102

Alignment with YeastPathways BIOTIN-SYNTHESIS-PWY and the PomBase model 67c10cc400002026. The module now models the pimelate-thioester supply and the KAPA-forming step as variant sets, because these are the steps that differ between bacteria, filamentous fungi and Saccharomyces; the BioA, BioD and BioB steps are conserved and only gain fungal exemplars. The Saccharomyces route was rebuilt after loss of the ancestral pathway: BIO1 arose by duplication of the PhyH-family gene YJR154W and BIO6 by duplication of the BioA gene BIO3 (PMID:18073433). Many S. cerevisiae strains, including S288C, lack BIO1 and BIO6 and are biotin auxotrophs; the BIO1 and BIO6 exemplars are therefore from strain A364a. BIO5 (KAPA/DAPA uptake), VHT1 (biotin uptake), BPL1 biotin-protein ligase, BirA-type regulation and the human biotin cycle (modules/biotin_cycle.yaml) are outside the module. S. pombe has no BioF, BioA or BioD family member and keeps only bio2, so it can make biotin only from imported dethiobiotin. Compartments: BIO2 and A. nidulans BioB are mitochondrial, A. nidulans BioF is peroxisomal, and UniProt also places A. nidulans BioDA in the mitochondrial matrix by similarity; the SGD GO-CAM places all yeast activities in cytosol. The bifunctional BioDA architecture is noted at the BioA and BioD steps rather than as a separate variant set, because the reactions and their order are unchanged. Molecular functions are attached only to leaf annotons. GO:0102130 retains its official label, malonyl-CoA methyltransferase activity, while its definition and RHEA:17105 grounding specify the physiological malonyl-ACP reaction modeled here. BioC uses NCBIfam:TIGR02072 because its current PANTHER subfamily is mislabeled as a mitochondrial arginine hydroxylase. The BioA family is now asserted at PTHR42684 because the fungal BIO3/BioDA proteins are in a different subfamily (SF3) from the bacterial exemplars (SF17).

Connections

bioC_step -> bioH_step Precedes
Two cycles of shared fatty-acid elongation convert the BioC product to pimeloyl-ACP methyl ester before BioH hydrolysis.
pimelate_thioester_supply -> bioF_step Provides Input For
The pimelate thioester (pimeloyl-ACP or pimeloyl-CoA) is the KAPA synthase substrate.
bioF_step -> bioA_step Precedes
bioA_step -> bioD_step Precedes
bioD_step -> bioB_step Precedes
Part 1: pimelate-thioester supply
Pimeloyl-ACP or pimeloyl-CoA formationMetabolic Pathwaypimelate_thioester_supply

Supplies the seven-carbon pimelate thioester that KAPA synthase condenses with L-alanine. The route differs between lineages.

Variant set: Pimelate-thioester supply routes by route (taxon) (Exactly One)
BioC-BioH route through fatty-acid synthesis (many bacteria)Metabolic Pathwaybioc_bioh_variant
Part 1: malonyl-ACP carboxyl methylation
Malonyl-ACP to malonyl-ACP methyl esterReactionbioC_step

Annotons

BioC malonyl-ACP O-methyltransferase
bioC_activity
Participant: Family: BioC malonyl-ACP O-methyltransferase family
Family:
BioC malonyl-ACP O-methyltransferase familyNCBIfam:TIGR02072
Representative Members: bioC (Pseudomonas putida KT2440)UniProtKB:Q88QW9 bioC (Escherichia coli K-12)UniProtKB:P12999
Required Function:
malonyl-ACP O-methyltransferase activityGO:0102130

Function

malonyl-ACP O-methyltransferase activityGO:0102130
Substrates: malonyl-[acyl-carrier protein] S-adenosyl-L-methionine
Products: malonyl-[acyl-carrier protein] methyl ester S-adenosyl-L-homocysteine

Masks the free carboxyl group so the pimelate precursor can be assembled by the shared fatty-acid-synthase elongation cycle.

Part 2: pathway-specific ester unmasking
Pimeloyl-ACP methyl ester to pimeloyl-ACPReactionbioH_step

Annotons

BioH pimeloyl-ACP methyl ester esterase
bioH_activity
Participant: Family: BioH pimeloyl-ACP methyl ester esterase family
Family:
BioH pimeloyl-ACP methyl ester esterase familyPANTHER:PTHR43194:SF5
Representative Members: bioH (Pseudomonas putida KT2440)UniProtKB:Q88QX0 bioH (Escherichia coli K-12)UniProtKB:P13001
Required Function:
pimeloyl-ACP methyl ester esterase activityGO:0090499

Function

pimeloyl-ACP methyl ester esterase activityGO:0090499
Substrates: pimeloyl-[acyl-carrier protein] methyl ester water
Products: pimeloyl-[acyl-carrier protein] methanol proton

Releases the free pimeloyl-ACP carboxyl group after the shared elongation machinery has generated the seven-carbon precursor.

Peroxisomal beta-oxidation route to pimeloyl-CoA (filamentous fungi)Metabolic Pathwayfungal_peroxisomal_beta_oxidation_variant

In Aspergillus nidulans and probably most fungi, pimeloyl-CoA is made by the peroxisomal beta-oxidation cycle (acyl-CoA oxidase AoxA and multifunctional protein FoxA) and used by a peroxisomal KAPA synthase. The beta-oxidation enzymes are shared machinery, not biotin-specific members, so no annoton is asserted (PMID:21998305).

BIO1-dependent, oxygen-requiring route (Saccharomyces yeasts)Reactionsaccharomyces_bio1_variant

Saccharomyces yeasts lack the peroxisomal BioF route and need BIO1, a PhyH-family (Fe(II)/2-oxoglutarate dioxygenase-like) protein that arose by duplication of YJR154W. Biotin synthesis by this route needs oxygen. The substrate and product of BIO1 are unknown.

Annotons

BIO1: pimelate-thioester supply (reaction unknown)
bio1_pimelate_supply_activity
Participant: Family: Saccharomyces BIO1 (PhyH family)
Family:
Saccharomyces BIO1 (PhyH family)PANTHER:PTHR21308
Representative Members: BIO1 (Saccharomyces cerevisiae A364a)UniProtKB:E9P9F6

Function

pimelate-thioester supply (catalytic activity unknown) SGD annotates BIO1 to 6-carboxyhexanoate-CoA ligase activity (GO:0042410) by sequence similarity, but BIO1 is a PhyH-family dioxygenase-like protein rather than an acyl-CoA ligase, and its reaction remains unresolved (PMID:32276977). No GO molecular-function term is asserted.

Required for formation of the pimelate moiety in Saccharomyces yeasts.

Part 2: 8-amino-7-oxononanoate formation
Pimelate thioester to 8-amino-7-oxononanoate (KAPA)ReactionbioF_step
Variant set: KAPA formation implementations by enzyme family and compartment (taxon) (Exactly One)
Bacterial BioF (pimeloyl-ACP)Reactionbacterial_biof_variant

Annotons

BioF 8-amino-7-oxononanoate synthase
bioF_activity
Participant: Family: proteobacterial BioF family
Family:
proteobacterial BioF familyPANTHER:PTHR13693:SF100
Representative Members: bioF (Pseudomonas putida KT2440)UniProtKB:Q88QX1 bioF (Escherichia coli K-12)UniProtKB:P12998
Required Function:
8-amino-7-oxononanoate synthase activityGO:0008710

Function

8-amino-7-oxononanoate synthase activityGO:0008710
Substrates: pimeloyl-[acyl-carrier protein] L-alanine proton
Products: 8-amino-7-oxononanoate holo-[acyl-carrier protein] carbon dioxide
Cofactors: pyridoxal 5'-phosphate

Commits the pimelate precursor to biotin ring assembly through a PLP-dependent decarboxylative condensation with L-alanine.

Peroxisomal fungal BioF (pimeloyl-CoA)Reactionfungal_peroxisomal_biof_variant

Annotons

Peroxisomal 8-amino-7-oxononanoate synthase (fungal BioF)
fungal_biof_activity
Participant: Family: fungal PTS1-bearing BioF subfamily
Family:
fungal PTS1-bearing BioF subfamilyPANTHER:PTHR13693:SF77
Representative Members: bioF (Aspergillus nidulans)UniProtKB:C8V1D1
Required Function:
8-amino-7-oxononanoate synthase activityGO:0008710

Function

8-amino-7-oxononanoate synthase activityGO:0008710
Substrates: pimeloyl-CoA L-alanine
Products: 8-amino-7-oxononanoate coenzyme A carbon dioxide
Cofactors: pyridoxal 5'-phosphate

Locations

peroxisomeGO:0005777

Condenses peroxisomal pimeloyl-CoA with L-alanine.

BIO6-dependent KAPA formation (Saccharomyces yeasts)Reactionsaccharomyces_bio6_variant

Annotons

BIO6: KAPA formation (BioA-paralogue)
bio6_kapa_formation_activity
Participant: Family: Saccharomyces BIO6 (BioA-like class-III aminotransferase)
Family:
Saccharomyces BIO6 (BioA-like class-III aminotransferase)PANTHER:PTHR42684 BIO6 is 52% identical to BIO3 (PMID:16269718) and is classified with BioA proteins (PTHR42684:SF17), not with the class-II BioF synthases.
Representative Members: BIO6 (Saccharomyces cerevisiae A364a)UniProtKB:E9P8E0

Function

8-amino-7-oxononanoate synthase activityGO:0008710 Genetic evidence places BIO6 before KAPA: KAPA rescues a bio6 mutant but not a bio3 mutant (PMID:16269718). SGD annotates BIO6 to GO:0008710 by sequence similarity (ISS), and later work refers to Bio6 as KAPA synthase (PMID:32276977), but the activity of purified BIO6 has not been reported.
Products: 8-amino-7-oxononanoate

Required for KAPA formation in Saccharomyces yeasts, which have no BioF orthologue.

Part 3: 7,8-diaminononanoate formation
8-amino-7-oxononanoate to 7,8-diaminononanoateReactionbioA_step

Annotons

BioA/BIO3 adenosylmethionine aminotransferase
bioA_activity
Participant: Family: BioA aminotransferase family
Family:
BioA aminotransferase familyPANTHER:PTHR42684 The bacterial exemplars are in subfamily SF17 and the fungal BIO3 and BioDA proteins in SF3, so the family-level id is used. The Saccharomyces BIO6 paralogue (SF17) is a member of this family but is modelled at the KAPA step.
Representative Members: bioA (Pseudomonas putida KT2440)UniProtKB:Q88D44 bioA (Escherichia coli K-12)UniProtKB:P12995 BIO3 (Saccharomyces cerevisiae)UniProtKB:P50277 bioDA (Aspergillus nidulans)UniProtKB:Q5AYI6
Required Function:
adenosylmethionine-8-amino-7-oxononanoate transaminase activityGO:0004015

Function

adenosylmethionine-8-amino-7-oxononanoate transaminase activityGO:0004015
Substrates: 8-amino-7-oxononanoate S-adenosyl-L-methionine
Products: 7,8-diaminononanoate S-adenosyl-4-methylsulfanyl-2-oxobutanoate
Cofactors: pyridoxal 5'-phosphate

Supplies the second amino group needed to close the ureido ring.

Part 4: dethiobiotin ring closure
7,8-diaminononanoate to dethiobiotinReactionbioD_step

Annotons

BioD/BIO4 dethiobiotin synthase
bioD_activity
Participant: Family: BioD dethiobiotin synthase family
Family:
BioD dethiobiotin synthase familyPANTHER:PTHR43210:SF5
Representative Members: bioD (Pseudomonas putida KT2440)UniProtKB:Q88QW8 bioD (Escherichia coli K-12)UniProtKB:P13000 BIO4 (Saccharomyces cerevisiae)UniProtKB:P53630
Required Function:
dethiobiotin synthase activityGO:0004141

Function

dethiobiotin synthase activityGO:0004141
Substrates: 7,8-diaminononanoate carbon dioxide ATP
Products: dethiobiotin ADP phosphate three protons
Cofactors: magnesium ion

ATP-dependent carboxylation and closure of the ureido ring. In filamentous fungi and plants this activity is the BioD domain of the bifunctional BioDA protein, which is classified only in the BioA PANTHER family and is therefore listed at the BioA step.

Part 5: sulfur insertion and biotin formation
Dethiobiotin to biotinReactionbioB_step

Annotons

BioB/BIO2 biotin synthase
bioB_activity
Participant: Family: BioB radical-SAM biotin synthase family
Family:
BioB radical-SAM biotin synthase familyPANTHER:PTHR22976
Representative Members: bioB (Pseudomonas putida KT2440)UniProtKB:Q88QX2 bioB (Escherichia coli K-12)UniProtKB:P12996 BIO2 (Saccharomyces cerevisiae)UniProtKB:P32451 bio2 (Schizosaccharomyces pombe)UniProtKB:O59778 bioB (Aspergillus nidulans)UniProtKB:Q5AYI7
Required Function:
biotin synthase activityGO:0004076

Function

biotin synthase activityGO:0004076
Substrates: dethiobiotin sulfur donor S-adenosyl-L-methionine reducing equivalents
Products: biotin 5'-deoxyadenosine L-methionine
Cofactors: 4 iron, 4 sulfur cluster 2 iron, 2 sulfur cluster

Inserts sulfur into dethiobiotin through radical-SAM chemistry to complete the biotin cofactor. The enzyme is cytosolic in bacteria and mitochondrial in fungi.