L-histidine biosynthesis (microbial)

De novo biosynthesis of L-histidine from PRPP and ATP through the conserved microbial His pathway. The module begins at the first committed ATP phosphoribosyltransferase reaction; PRPP production is shared upstream metabolism and is intentionally outside the module boundary. The pathway returns the ATP-derived purine ring to nucleotide metabolism as AICAR during the HisF-HisH imidazole-glycerol-phosphate synthase reaction. Its enzyme architecture varies across lineages: short-form HisG uses a separate HisZ regulatory subunit, the phosphoribosyl-ATP diphosphatase and phosphoribosyl-AMP cyclohydrolase can be separate or fused, and histidinol-phosphate phosphatase activity has arisen in several unrelated families. The terminal HisD enzyme performs two successive NAD+-dependent oxidations through histidinal to produce L-histidine.

MODULE:histidine_biosynthesisDRAFTMetabolic Pathwaymodules/histidine_biosynthesis.yaml
L-histidine biosynthetic processGO:0000105
GapMind:aa
GapMind for amino acid biosynthesis
Step set and characterized-protein groundings derive from the GapMind amino-acid biosynthesis pathway definition his.steps (PaperBLAST, Price & Arkin, LBL).
MetaCyc:HISTSYN-PWY
L-histidine biosynthesis
GapMind bases the histidine pathway on the MetaCyc pathway HISTSYN-PWY.
GO:0000105
L-histidine biosynthetic process
The module is grounded in the GO biological-process term for histidine biosynthesis.
KEGG:ppu00340
Pseudomonas putida KT2440 histidine metabolism
The PSEPK ppu00340 instance grounds the pathway with hisG/hisZ, hisE, hisI, hisA, hisF/hisH, hisB, hisC, PP_3157/PP_5147, and hisD while also containing histidine-catabolism and other pathway-map spillover genes.
file:projects/P_PUTIDA/deep-research/PSEPK__histidine_biosynthesis__ppu00340-deep-research-openscientist.md
OpenScientist module/pathway/taxon report for PSEPK histidine biosynthesis
Supports the biosynthesis boundary, ordered catalytic activities, HisG-HisZ and HisF-HisH architectures, and exclusion of Hut catabolism from this module. Its recommendation to exclude PP_5147 is not adopted: the report did not account for the direct Pseudomonas HAD-family histidinol-phosphatase evidence and close PA0335 orthology documented below.
PMID:28720084
Sequence-based identification of inositol monophosphatase-like histidinol-phosphate phosphatases (HisN) in Corynebacterium glutamicum, Actinobacteria, and beyond
Defines sequence motifs and HMMs that distinguish IMPase-like HisN phosphatases from related inactive substrate classes and finds this family beyond Actinobacteria, including Proteobacteria.
PMID:31862725
PA0335, a Gene Encoding Histidinol Phosphate Phosphatase, Mediates Histidine Auxotrophy in Pseudomonas aeruginosa
Provides genetic and biochemical evidence for the monofunctional Pseudomonas HAD-family histidinol-phosphate phosphatase represented by PA0335.
file:projects/P_PUTIDA/data/psepk_pathway_membership.tsv
PSEPK pathway membership table
The local partition provides the accession and locus-tag mapping used to distinguish the biosynthetic core from Hut catabolism and unrelated ppu00340 members.
12Nodes
9Parts
1Variant Sets
2Variants
12Annotons
8Connections

Derived QC

Recommended-field compliance

60.0% recommended fields populated
  • module.knowledge_gaps[0] · status (0/1)
  • module.knowledge_gaps[0] · provenance (0/1)

Module deep research

✗ none found

No MODULE:histidine_biosynthesis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

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.

  • hisG_step → pr_atp_diphosphatase_step [NOT_CHECKED]
  • pr_atp_diphosphatase_step → pr_amp_cyclohydrolase_step [NOT_CHECKED]
  • pr_amp_cyclohydrolase_step → hisA_step [NOT_CHECKED]
  • hisA_step → igp_synthase_step [NOT_CHECKED]
  • igp_synthase_step → hisB_step [NOT_CHECKED]
  • hisB_step → hisC_step [NOT_CHECKED]
  • hisC_step → hisN_step [NOT_CHECKED]
  • hisN_step → hisD_step [NOT_CHECKED]

Gene-review completeness (12/13 grounded genes reviewed)

12 complete review(s) · 10 with deep research · 1 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
hisA Q88R42 ✓ ✓ ✓
hisB Q88R45 ✓ ✓ ✓
hisC Q88P86 ✓ ✓ ✓
hisD P59400 ✓ ✓ ✓
hisE Q88D14 ✓ ✓ ✗
hisF Q88R41 ✓ ✓ ✗
hisG Q88P87 ✓ ✓ ✓
hisH Q88R44 ✓ ✓ ✓
hisI Q88D15 ✓ ✓ ✓
hisZ Q88DD7 ✓ ✓ ✓
PP_3157 Q88I44 ✓ ✓ ✓
PP_5147 Q88CN3 ✓ ✓ ✓
Pseudomonas aeruginosa PA0335 Q9I6F6 ✗ — —

Details

L-histidine biosynthesisMetabolic Pathwayhistidine_biosynthesis
L-histidine biosynthetic processGO:0000105

The reusable reaction backbone comes from GapMind and MetaCyc, with GO and reaction identifiers checked against the local gene records. This curation removes shared PRPP production from the module core, places all molecular functions on leaf annotons, grounds every leaf with a PSEPK UniProt exemplar, and uses activity-based names where HisE/HisI gene nomenclature varies. In KT2440, Q88D14 is the standalone phosphoribosyl-ATP diphosphatase and Q88D15 is the standalone phosphoribosyl-AMP cyclohydrolase. Fusion notes retain the reusable HisIE, HisB, and PriA alternatives without treating those architectures as PSEPK-specific facts. The commissioned OpenScientist taxon report independently supports the pathway boundary and satisfiability but its PP_5147 candidate ranking is superseded here by the gene-level primary-evidence review.

Connections

hisB_step -> hisC_step Precedes
hisC_step -> hisN_step Precedes
hisN_step -> hisD_step Precedes
Part 1: first committed step
PRPP to phosphoribosyl-ATPReactionhisG_step

Annotons

ATP phosphoribosyltransferase catalytic subunit
hisG_activity
Participant: Family: HisG ATP phosphoribosyltransferase family
Family:
HisG ATP phosphoribosyltransferase familyPANTHER:PTHR21403:SF8
Representative Members: PSEPK HisGUniProtKB:Q88P87
Required Function:
ATP phosphoribosyltransferase activityGO:0003879

Function

ATP phosphoribosyltransferase activityGO:0003879
Substrates: 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) ATP
Products: N1-(5-phospho-beta-D-ribosyl)-ATP (phosphoribosyl-ATP) diphosphate

Catalyzes the first committed step of histidine biosynthesis. Long- form HisG proteins carry their own regulatory region, whereas short-form HisG proteins such as the PSEPK exemplar use a separate HisZ regulatory subunit.

HisZ regulatory subunit of short-form ATPPRT
hisZ_regulatory_activity
Participant: Family: HisZ regulatory-subunit family
Family:
HisZ regulatory-subunit familyInterPro:IPR004517
Representative Members: PSEPK HisZUniProtKB:Q88DD7

Function

ATP phosphoribosyltransferase regulatory subunit activity Non-catalytic activation and L-histidine-responsive feedback regulation of a short-form HisG catalytic subunit.

Processes

L-histidine biosynthetic processGO:0000105

Required in the short-form ATPPRT architecture exemplified by PSEPK; not a universal extra subunit of long-form HisG enzymes.

Part 2: phosphoribosyl-ATP diphosphatase
Phosphoribosyl-ATP to phosphoribosyl-AMPReactionpr_atp_diphosphatase_step

Annotons

Phosphoribosyl-ATP diphosphatase
pr_atp_diphosphatase_activity
Participant: Family: HisE phosphoribosyl-ATP diphosphatase family
Family:
HisE phosphoribosyl-ATP diphosphatase familyInterPro:IPR008179
Representative Members: PSEPK HisEUniProtKB:Q88D14
Required Function:
phosphoribosyl-ATP diphosphatase activityGO:0004636

Function

phosphoribosyl-ATP diphosphatase activityGO:0004636
Substrates: N1-(5-phospho-beta-D-ribosyl)-ATP (phosphoribosyl-ATP) water
Products: 1-(5-phospho-beta-D-ribosyl)-AMP (phosphoribosyl-AMP) diphosphate

PSEPK names the standalone diphosphatase HisE. Gene symbols vary across taxa, and this activity can be fused to the following cyclohydrolase in a bifunctional protein.

Part 3: phosphoribosyl-AMP cyclohydrolase
Phosphoribosyl-AMP to ProFARReactionpr_amp_cyclohydrolase_step

Annotons

Phosphoribosyl-AMP cyclohydrolase
pr_amp_cyclohydrolase_activity
Participant: Family: phosphoribosyl-AMP cyclohydrolase family
Family:
phosphoribosyl-AMP cyclohydrolase familyPfam:PF01502
Representative Members: PSEPK HisIUniProtKB:Q88D15
Required Function:
phosphoribosyl-AMP cyclohydrolase activityGO:0004635

Function

phosphoribosyl-AMP cyclohydrolase activityGO:0004635
Substrates: 1-(5-phospho-beta-D-ribosyl)-AMP (phosphoribosyl-AMP) water
Products: 5-[(5-phospho-1-deoxy-D-ribulos-1-ylamino)methylideneamino]-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide (ProFAR)

PSEPK names the standalone cyclohydrolase HisI. This activity can be fused to the preceding diphosphatase in other lineages.

Part 4: amino-isomerase
ProFAR to PRFARReactionhisA_step

Annotons

HisA ProFAR isomerase
hisA_activity
Participant: Family: bacterial HisA ProFAR isomerase family
Family:
bacterial HisA ProFAR isomerase familyPANTHER:PTHR43090:SF2
Representative Members: PSEPK HisAUniProtKB:Q88R42
Required Function:
1-(5-phosphoribosyl)-5-[(5-phosphoribosylamino)methylideneamino]imidazole-4-carboxamide isomerase activityGO:0003949

Function

ProFAR isomerase activityGO:0003949
Substrates: ProFAR
Products: N-[(5-phospho-1-deoxy-D-ribulos-1-yl)amino]methylidene-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide (PRFAR)

HisA belongs to the (beta/alpha)8 TIM-barrel HisA/TrpF superfamily; in actinobacteria the bifunctional PriA enzyme performs both HisA and TrpF (PRA isomerase) reactions.

Part 5: imidazole-glycerol-phosphate synthase (glutamine amidotransferase)
PRFAR to imidazole-glycerol-phosphate + AICARReactionigp_synthase_step

Imidazole-glycerol-phosphate (IGP) synthase is a glutamine amidotransferase formed by a cyclase subunit (HisF) and a glutaminase / amidotransferase subunit (HisH). Glutamine hydrolysed by HisH supplies ammonia through an internal channel to the HisF active site, which cleaves PRFAR into IGP and AICAR. AICAR re-enters purine biosynthesis, linking histidine and nucleotide metabolism.

Annotons

hisF: IGP synthase, cyclase subunit
hisF_activity
Participant: Family: imidazole-glycerol-phosphate synthase cyclase subunit HisF
Family:
imidazole-glycerol-phosphate synthase cyclase subunit HisFNCBIfam:TIGR00735
Representative Members: PSEPK HisFUniProtKB:Q88R41
Required Function:
imidazoleglycerol-phosphate synthase activityGO:0000107

Function

imidazoleglycerol-phosphate synthase activityGO:0000107
Substrates: PRFAR L-glutamine
Products: D-erythro-imidazole-glycerol 3-phosphate (IGP) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) L-glutamate

Cyclase subunit; cleaves PRFAR to IGP and AICAR using channelled ammonia.

hisH: IGP synthase, glutamine amidotransferase subunit
hisH_activity
Participant: Family: imidazole-glycerol-phosphate synthase amidotransferase subunit HisH
Family:
imidazole-glycerol-phosphate synthase amidotransferase subunit HisHNCBIfam:TIGR01855
Representative Members: PSEPK HisHUniProtKB:Q88R44
Required Function:
imidazoleglycerol-phosphate synthase activityGO:0000107

Function

imidazoleglycerol-phosphate synthase activityGO:0000107
Substrates: L-glutamine water
Products: L-glutamate ammonia

Glutaminase subunit; hydrolyses L-glutamine to supply ammonia to the HisF active site. Has no productive activity in isolation.

Part 6: dehydratase
IGP to imidazole-acetol phosphateReactionhisB_step

Annotons

HisB imidazoleglycerol-phosphate dehydratase
hisB_activity
Participant: Family: HisB imidazoleglycerol-phosphate dehydratase family
Family:
HisB imidazoleglycerol-phosphate dehydratase familyPANTHER:PTHR23133:SF2
Representative Members: PSEPK HisBUniProtKB:Q88R45
Required Function:
imidazoleglycerol-phosphate dehydratase activityGO:0004424

Function

imidazoleglycerol-phosphate dehydratase activityGO:0004424
Substrates: D-erythro-imidazole-glycerol 3-phosphate (IGP)
Products: 3-(imidazol-4-yl)-2-oxopropyl phosphate (imidazole-acetol phosphate) water

In enteric bacteria such as E. coli this activity is the C-terminal domain of a bifunctional HisB protein whose N-terminal HAD domain provides histidinol-phosphate phosphatase activity.

Part 7: transaminase
Imidazole-acetol phosphate to L-histidinol phosphateReactionhisC_step

Annotons

HisC histidinol-phosphate aminotransferase
hisC_activity
Participant: Family: HisC histidinol-phosphate aminotransferase family
Family:
HisC histidinol-phosphate aminotransferase familyPANTHER:PTHR43643:SF3
Representative Members: PSEPK HisCUniProtKB:Q88P86
Required Function:
histidinol-phosphate aminotransferase activityGO:0004400

Function

histidinol-phosphate aminotransferase activityGO:0004400
Substrates: 3-(imidazol-4-yl)-2-oxopropyl phosphate (imidazole-acetol phosphate) L-glutamate
Products: L-histidinol phosphate 2-oxoglutarate
Cofactors: pyridoxal 5'-phosphate

PLP-dependent aminotransferase. In Bacillus subtilis and some related bacteria this activity is provided by a gene historically mislabelled hisH and now referred to as HisC.

Part 8: phosphatase
L-histidinol phosphate to L-histidinolReactionhisN_step

Histidinol-phosphate phosphatase activity has evolved independently in several phosphatase families. A pathway instance requires at least one implementation, but paralogous or unrelated enzymes can coexist and provide overlapping activity.

Variant set: Histidinol-phosphate phosphatase enzyme-family variants by enzyme family (One Or More)

The IMPase-like HisN and HAD-like implementations are modeled explicitly because both have strongly supported PSEPK exemplars. PHP-family and fused enterobacterial HisB implementations remain valid alternatives in other lineages but are not expanded here.

IMPase-like HisN implementationReactionimpase_hisn_variant

Annotons

IMPase-like HisN histidinol-phosphate phosphatase
impase_hisn_activity
Participant: Family: IMPase-like HisN family
Family:
IMPase-like HisN familyNCBIfam:TIGR02067
Representative Members: PSEPK PP_3157UniProtKB:Q88I44
Required Function:
histidinol-phosphatase activityGO:0004401

Function

histidinol-phosphatase activityGO:0004401
Substrates: L-histidinol phosphate water
Products: L-histidinol phosphate

A monofunctional metal-dependent IMPase-superfamily implementation identified by the HisN-specific family model rather than generic IMPase similarity.

Monofunctional HAD-family implementationReactionhad_holpase_variant

Annotons

HAD-family histidinol-phosphate phosphatase
had_holpase_activity
Participant: Family: monofunctional HAD-family histidinol-phosphate phosphatases
Family:
monofunctional HAD-family histidinol-phosphate phosphatasesNCBIfam:TIGR01490
Representative Members: PSEPK PP_5147UniProtKB:Q88CN3 Pseudomonas aeruginosa PA0335UniProtKB:Q9I6F6
Required Function:
histidinol-phosphatase activityGO:0004401

Function

histidinol-phosphatase activityGO:0004401
Substrates: L-histidinol phosphate water
Products: L-histidinol phosphate

A standalone HAD-superfamily implementation distinct from the N-terminal HAD domain fused into enterobacterial HisB.

Part 9: terminal bifunctional dehydrogenase
L-histidinol to L-histidineReactionhisD_step

HisD is a bifunctional NAD+-dependent dehydrogenase that oxidises L-histidinol to L-histidine in two steps via an L-histidinal intermediate, consuming two equivalents of NAD+.

Annotons

HisD histidinol dehydrogenase
hisD_activity
Participant: Family: monofunctional HisD histidinol dehydrogenase family
Family:
monofunctional HisD histidinol dehydrogenase familyInterPro:IPR022695
Representative Members: PSEPK HisDUniProtKB:P59400
Required Function:
histidinol dehydrogenase activityGO:0004399

Function

histidinol dehydrogenase activityGO:0004399
Substrates: L-histidinol NAD+ (2 equivalents) water
Products: L-histidine NADH (2 equivalents)

Four-electron oxidation of the histidinol alcohol to the histidine carboxylate, via histidinal.