L-histidine biosynthesis (microbial)

De novo biosynthesis of L-histidine from 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and ATP. This is an ancient, largely linear pathway of ten enzymatic activities that is broadly conserved across bacteria, archaea, fungi, and plants, and is the canonical microbial route. The pathway is metabolically unusual in that its purine-like intermediates connect it to nucleotide metabolism: the imidazole-glycerol-phosphate synthase step releases AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), a purine-biosynthesis intermediate, recycling the adenine ring of ATP back into the nucleotide pool. Several activities are commonly fused or bifunctional in microbes (e.g. the HisIE pyrophosphohydrolase/cyclohydrolase, and the HisB dehydratase fused to a histidinol-phosphate phosphatase domain in enteric bacteria), and the terminal HisD histidinol dehydrogenase performs two successive NAD+-dependent oxidations through a histidinal intermediate. The pathway is energetically expensive and is tightly regulated, classically by feedback inhibition of the first committed enzyme (ATP phosphoribosyltransferase, HisG) by 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.
11Nodes
10Parts
0Variant Sets
0Variants
11Annotons
9Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

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

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (0/0 grounded genes reviewed)

No concrete UniProt-grounded genes in this module.

Details

Context
cytosolGO:0005829
L-histidine biosynthesisMetabolic Pathwayhistidine_biosynthesis
L-histidine biosynthetic processGO:0000105
Context
cytosolGO:0005829

Backbone and characterized-protein groundings were mined from GapMind his.steps and ModelSEED (see modules/experimental/gapmind-mining/), then curated: GO molecular-function terms were verified via QuickGO, reaction chemistry and bifunctional-enzyme notes were added, and one incorrect ModelSEED EC auto-mapping (hisC) was corrected. The HisIE, HisB, and PriA fusion notes flag where a single microbial protein covers more than one step.

Connections

prs_step -> hisG_step Provides Input For
PRPP from the diphosphokinase feeds the first committed step.
hisG_step -> hisI_step Precedes
hisI_step -> hisE_step Precedes
hisE_step -> hisA_step Precedes
hisB_step -> hisC_step Precedes
hisC_step -> hisN_step Precedes
hisN_step -> hisD_step Precedes
Part 1: PRPP supply (shared, not histidine-specific)
Ribose-5-phosphate to PRPPReactionprs_step

Annotons

prs: ribose-phosphate diphosphokinase
prs_activity
Participant: Any With Function: ribose phosphate diphosphokinase activity
Required Function:
ribose phosphate diphosphokinase activityGO:0004749

Function

ribose phosphate diphosphokinase activityGO:0004749
Substrates: D-ribose 5-phosphate ATP
Products: 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) AMP

Provides PRPP, the entry metabolite. This activity is shared with nucleotide and tryptophan biosynthesis and is not specific to the histidine pathway, so it is included as context rather than as a committed histidine step.

Part 2: first committed step
PRPP to phosphoribosyl-ATPReactionhisG_step

Annotons

hisG: ATP phosphoribosyltransferase
hisG_activity
Participant: Any With Function: ATP phosphoribosyltransferase activity
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

First and committed step of histidine biosynthesis; the classic site of feedback inhibition by L-histidine.

Part 3: pyrophosphohydrolase (often HisIE bifunctional)
Phosphoribosyl-ATP to phosphoribosyl-AMPReactionhisI_step

Annotons

hisI: phosphoribosyl-ATP diphosphatase
hisI_activity
Participant: Any With Function: phosphoribosyl-ATP diphosphatase activity
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

In many bacteria the HisI pyrophosphohydrolase and HisE cyclohydrolase activities reside on a single bifunctional HisIE protein.

Part 4: cyclohydrolase (often HisIE bifunctional)
Phosphoribosyl-AMP to ProFARReactionhisE_step

Annotons

hisE: phosphoribosyl-AMP cyclohydrolase
hisE_activity
Participant: Family: phosphoribosyl-AMP cyclohydrolase (HisE / HisIE)
Family:
phosphoribosyl-AMP cyclohydrolase (HisE / HisIE)Pfam:PF01502
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)
Part 5: amino-isomerase
ProFAR to PRFARReactionhisA_step

Annotons

hisA: ProFAR isomerase
hisA_activity
Participant: Any With Function: 1-(5-phosphoribosyl)-5-[(5-phosphoribosylamino)methylideneamino]imidazole-4-carboxamide isomerase activity
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 6: 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
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
Required Function:
imidazoleglycerol-phosphate synthase activityGO:0000107

Function

imidazoleglycerol-phosphate synthase activityGO:0000107
Cofactors: L-glutamine (ammonia donor)

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

Part 7: dehydratase
IGP to imidazole-acetol phosphateReactionhisB_step

Annotons

hisB: imidazoleglycerol-phosphate dehydratase
hisB_activity
Participant: Any With Function: imidazoleglycerol-phosphate dehydratase activity
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 N-terminal domain of a bifunctional HisB protein whose C-terminal domain provides the HisN-type histidinol-phosphate phosphatase activity.

Part 8: transaminase
Imidazole-acetol phosphate to L-histidinol phosphateReactionhisC_step

Annotons

hisC: histidinol-phosphate aminotransferase
hisC_activity
Participant: Any With Function: histidinol-phosphate aminotransferase activity
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 9: phosphatase
L-histidinol phosphate to L-histidinolReactionhisN_step

Annotons

hisN: histidinol-phosphate phosphatase
hisN_activity
Participant: Any With Function: histidinol-phosphatase activity
Required Function:
histidinol-phosphatase activityGO:0004401

Function

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

Histidinol-phosphate phosphatase activity has evolved repeatedly in several unrelated phosphatase families (PHP, inositol-monophosphatase-like, and HAD-like). In Bacillus subtilis it is HisJ; in enteric bacteria it is the C-terminal domain of bifunctional HisB.

Part 10: 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: Any With Function: histidinol dehydrogenase activity
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.