L-histidine biosynthesis

De novo biosynthesis of L-histidine from PRPP and ATP through the conserved ten-reaction His pathway found in bacteria, archaea, fungi and plants. 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 imidazole-glycerol-phosphate synthase reaction, which couples histidine and purine biosynthesis. The reaction chain is invariant, but its enzyme architecture varies widely across lineages: ATP phosphoribosyltransferase exists as a short-form catalytic subunit with a separate HisZ regulatory subunit or as a long-form single chain; the phosphoribosyl-ATP diphosphatase and phosphoribosyl-AMP cyclohydrolase can be separate proteins, a bifunctional HisIE protein, or domains of a trifunctional protein that also carries histidinol dehydrogenase (as in budding yeast); the glutaminase and cyclase halves of imidazole-glycerol-phosphate synthase can be separate HisH and HisF subunits or a single fused HisHF chain (as in fungi); and histidinol-phosphate phosphatase activity has arisen in several unrelated families (IMPase-like, HAD and PHP). The terminal histidinol dehydrogenase 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.
YeastPathways:HISTSYN-PWY
L-histidine biosynthesis (S. cerevisiae, SGD YeastPathways)
The SGD YeastCyc pathway lists the ten histidine-biosynthesis reactions with HIS1, HIS4 (diphosphatase, cyclohydrolase and both histidinol dehydrogenase half-reactions), HIS6, HIS7, HIS3, HIS5 and HIS2 as catalysts. All seven gene assignments were retained after review.
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 treated as an unresolved candidate call: PA0335 establishes a Pseudomonas HAD-family implementation, but the cached evidence does not establish PP_5147 orthology or substrate specificity.
PMID:8852895
Histidine biosynthetic pathway and genes: structure, regulation, and evolution.
Review of the histidine pathway, its genes and their evolution across microbes; cited by YeastPathways for HISTSYN-PWY.
PMID:14190241
GENE-ENZYME RELATIONS IN HISTIDINE BIOSYNTHESIS IN YEAST.
Each S. cerevisiae histidine mutant class was correlated with a particular pathway step, establishing the yeast gene-enzyme map.
PMID:379004
The product of the his4 gene cluster in Saccharomyces cerevisiae. A trifunctional polypeptide.
HIS4 encodes a single 95-kDa polypeptide carrying phosphoribosyl-AMP cyclohydrolase, phosphoribosyl-ATP pyrophosphohydrolase and histidinol dehydrogenase activities.
PMID:8366040
Cloning, primary structure, and regulation of the HIS7 gene encoding a bifunctional glutamine amidotransferase: cyclase from Saccharomyces cerevisiae.
HIS7 encodes a fused glutamine amidotransferase (HisH-like) and cyclase (HisF-like) protein that complements E. coli hisH and hisF mutants.
PMID:11591353
Crystal structure of imidazole glycerol phosphate synthase: a tunnel through a (beta/alpha)8 barrel joins two active sites.
The structure of the yeast single-chain IGP synthase shows the glutaminase and cyclase domains joined by an ammonia tunnel.
PMID:10322033
Histidinol phosphate phosphatase, catalyzing the penultimate step of the histidine biosynthesis pathway, is encoded by ytvP (hisJ) in Bacillus subtilis.
Defines the HisJ (PHP-family) histidinol-phosphate phosphatases, which include the S. cerevisiae and S. pombe enzymes and are not homologous to the enterobacterial HisB phosphatase.
PMID:8299169
Cloning and manipulation of the Schizosaccharomyces pombe his7+ gene as a new selectable marker for molecular genetic studies.
S. pombe his7+ complements an E. coli hisI mutation, supporting its assignment as the HisIE cyclohydrolase/diphosphatase protein.
PMID:15744050
Revisiting purine-histidine cross-pathway regulation in Saccharomyces cerevisiae: a central role for a small molecule.
AICAR, the purine-pathway co-product of the IGP synthase reaction, is synthesised by both the AMP and histidine pathways in yeast and acts as a regulatory molecule linking them.
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.
21Nodes
8Parts
5Variant Sets
12Variants
20Annotons
7Connections

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

✓ 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 → hisie_steps [NOT_CHECKED]
  • hisie_steps → 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]

Function consistency and core coverage

25 gene-function check(s) reflected in core functions · 0 conflict(s) · 25 evidence or coverage gap(s) (53 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
short_hisG_activity hisG (Pseudomonas putida KT2440)
UniProtKB:Q88P87
Family Representative 		ATP phosphoribosyltransferase activity
GO:0003879 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisZ_regulatory_activity hisZ (Pseudomonas putida KT2440)
UniProtKB:Q88DD7
Family Representative 		ATP phosphoribosyltransferase regulatory subunit activity
No function ID 		No Function Id
A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
long_hisG_activity hisG (Mycobacterium tuberculosis)
UniProtKB:P9WMN1
Family Representative 		ATP phosphoribosyltransferase activity
GO:0003879 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
long_hisG_activity HIS1 (Saccharomyces cerevisiae)
UniProtKB:P00498
Family Representative 		ATP phosphoribosyltransferase activity
GO:0003879 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
long_hisG_activity his1 (Schizosaccharomyces pombe)
UniProtKB:P40373
Family Representative 		ATP phosphoribosyltransferase activity
GO:0003879 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pr_atp_diphosphatase_activity hisE (Pseudomonas putida KT2440)
UniProtKB:Q88D14
Family Representative 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pr_amp_cyclohydrolase_activity hisI (Pseudomonas putida KT2440)
UniProtKB:Q88D15
Family Representative 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bifunctional_hisie_diphosphatase_activity his7 (Schizosaccharomyces pombe)
UniProtKB:O59667
Family Representative 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bifunctional_hisie_cyclohydrolase_activity his7 (Schizosaccharomyces pombe)
UniProtKB:O59667
Family Representative 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
trifunctional_hisie_diphosphatase_activity HIS4 (Saccharomyces cerevisiae)
UniProtKB:P00815
Family Representative 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
trifunctional_hisie_cyclohydrolase_activity HIS4 (Saccharomyces cerevisiae)
UniProtKB:P00815
Family Representative 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisA_activity hisA (Pseudomonas putida KT2440)
UniProtKB:Q88R42
Family Representative 		ProFAR isomerase activity
GO:0003949 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisA_activity HIS6 (Saccharomyces cerevisiae)
UniProtKB:P40545
Family Representative 		ProFAR isomerase activity
GO:0003949 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisA_activity his6 (Schizosaccharomyces pombe)
UniProtKB:Q10184
Family Representative 		ProFAR isomerase activity
GO:0003949 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisF_activity hisF (Pseudomonas putida KT2440)
UniProtKB:Q88R41
Family Representative 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
hisH_activity hisH (Pseudomonas putida KT2440)
UniProtKB:Q88R44
Family Representative 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
fused_hishf_activity HIS7 (Saccharomyces cerevisiae)
UniProtKB:P33734
Family Representative 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_hishf_activity his4 (Schizosaccharomyces pombe)
UniProtKB:O94303
Family Representative 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisB_activity hisB (Pseudomonas putida KT2440)
UniProtKB:Q88R45
Family Representative 		imidazoleglycerol-phosphate dehydratase activity
GO:0004424 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisB_activity HIS3 (Saccharomyces cerevisiae)
UniProtKB:P06633
Family Representative 		imidazoleglycerol-phosphate dehydratase activity
GO:0004424 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisB_activity his5 (Schizosaccharomyces pombe)
UniProtKB:P40374
Family Representative 		imidazoleglycerol-phosphate dehydratase activity
GO:0004424 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisC_activity hisC (Pseudomonas putida KT2440)
UniProtKB:Q88P86
Family Representative 		histidinol-phosphate aminotransferase activity
GO:0004400 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisC_activity HIS5 (Saccharomyces cerevisiae)
UniProtKB:P07172
Family Representative 		histidinol-phosphate aminotransferase activity
GO:0004400 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisC_activity his3 (Schizosaccharomyces pombe)
UniProtKB:P36605
Family Representative 		histidinol-phosphate aminotransferase activity
GO:0004400 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
impase_hisn_activity PP_3157 (Pseudomonas putida KT2440)
UniProtKB:Q88I44
Family Representative 		histidinol-phosphatase activity
GO:0004401 		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.
had_holpase_activity PP_5147 (Pseudomonas putida KT2440)
UniProtKB:Q88CN3
Family Representative 		histidinol-phosphatase activity
GO:0004401 		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.
had_holpase_activity PA0335 (Pseudomonas aeruginosa)
UniProtKB:Q9I6F6
Family Representative 		histidinol-phosphatase activity
GO:0004401 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
php_hisj_activity hisJ (Bacillus subtilis)
UniProtKB:O34411
Family Representative 		histidinol-phosphatase activity
GO:0004401 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
php_hisj_activity HIS2 (Saccharomyces cerevisiae)
UniProtKB:P38635
Family Representative 		histidinol-phosphatase activity
GO:0004401 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
php_hisj_activity SPCC1672.01 (Schizosaccharomyces pombe)
UniProtKB:O14059
Family Representative 		histidinol-phosphatase activity
GO:0004401 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisD_activity hisD (Pseudomonas putida KT2440)
UniProtKB:P59400
Family Representative 		histidinol dehydrogenase activity
GO:0004399 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hisD_activity his2 (Schizosaccharomyces pombe)
UniProtKB:Q9P777
Family Representative 		histidinol dehydrogenase activity
GO:0004399 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
trifunctional_hisd_activity HIS4 (Saccharomyces cerevisiae)
UniProtKB:P00815
Family Representative 		histidinol dehydrogenase activity
GO:0004399 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
short_hisG_activity short-form HisG ATP phosphoribosyltransferase family
InterPro:IPR024893
Family 		ATP phosphoribosyltransferase activity
GO:0003879 		Family Review Missing
No supported structured family review is available for InterPro:IPR024893.
hisZ_regulatory_activity HisZ regulatory-subunit family
InterPro:IPR004517
Family 		ATP phosphoribosyltransferase regulatory subunit activity
No function ID 		No Function Id
The family function has no GO identifier for comparison; prose is not matched.
long_hisG_activity long-form HisG ATP phosphoribosyltransferase family
InterPro:IPR020621
Family 		ATP phosphoribosyltransferase activity
GO:0003879 		Family Review Missing
No supported structured family review is available for InterPro:IPR020621.
pr_atp_diphosphatase_activity HisE phosphoribosyl-ATP diphosphatase family
InterPro:IPR008179
Family 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Family Review Missing
No supported structured family review is available for InterPro:IPR008179.
pr_amp_cyclohydrolase_activity phosphoribosyl-AMP cyclohydrolase family
InterPro:IPR026660
Family 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Family Review Missing
No supported structured family review is available for InterPro:IPR026660.
bifunctional_hisie_diphosphatase_activity bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Family 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Family Id Missing
The family has no identifier linking it to a curated family review.
bifunctional_hisie_cyclohydrolase_activity bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Family 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Family Id Missing
The family has no identifier linking it to a curated family review.
trifunctional_hisie_diphosphatase_activity histidine biosynthesis trifunctional protein family
InterPro:IPR016298
Family 		phosphoribosyl-ATP diphosphatase activity
GO:0004636 		Family Review Missing
No supported structured family review is available for InterPro:IPR016298.
trifunctional_hisie_cyclohydrolase_activity histidine biosynthesis trifunctional protein family
InterPro:IPR016298
Family 		phosphoribosyl-AMP cyclohydrolase activity
GO:0004635 		Family Review Missing
No supported structured family review is available for InterPro:IPR016298.
hisA_activity HisA ProFAR isomerase family
PANTHER:PTHR43090:SF2
Family 		ProFAR isomerase activity
GO:0003949 		Family Supported
Family review supports GO:0003949 FAMILY_WIDE. Asserted by histidine_biosynthesis; accepted by HIS6, SPAC3F10.09 and P. putida hisA.
hisF_activity imidazole-glycerol-phosphate synthase cyclase subunit HisF
NCBIfam:TIGR00735
Family 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR00735.
hisH_activity imidazole-glycerol-phosphate synthase amidotransferase subunit HisH
NCBIfam:TIGR01855
Family 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR01855.
fused_hishf_activity single-chain HisHF IGP synthase family
InterPro:IPR014640
Family 		imidazoleglycerol-phosphate synthase activity
GO:0000107 		Family Review Missing
No supported structured family review is available for InterPro:IPR014640.
hisB_activity HisB imidazoleglycerol-phosphate dehydratase family
PANTHER:PTHR23133:SF2
Family 		imidazoleglycerol-phosphate dehydratase activity
GO:0004424 		Family Supported
Family review supports GO:0004424 FAMILY_WIDE. Asserted by histidine_biosynthesis (SF2); accepted by HisB, HIS3 and his5.
hisC_activity HisC histidinol-phosphate aminotransferase family
InterPro:IPR005861
Family 		histidinol-phosphate aminotransferase activity
GO:0004400 		Family Review Missing
No supported structured family review is available for InterPro:IPR005861.
impase_hisn_activity IMPase-like HisN family
NCBIfam:TIGR02067
Family 		histidinol-phosphatase activity
GO:0004401 		Family Review Missing
No supported structured family review is available for NCBIfam:TIGR02067.
had_holpase_activity monofunctional HAD-family histidinol-phosphate phosphatases
Family 		histidinol-phosphatase activity
GO:0004401 		Family Id Missing
The family has no identifier linking it to a curated family review.
php_hisj_activity PHP-family HisJ histidinol-phosphatases
PANTHER:PTHR21039:SF0
Family 		histidinol-phosphatase activity
GO:0004401 		Family Supported
Family review supports GO:0004401 FAMILY_WIDE. Asserted by histidine_biosynthesis (SF0); accepted by HIS2 and SPCC1672.01.
hisD_activity monofunctional HisD histidinol dehydrogenase family
InterPro:IPR022695
Family 		histidinol dehydrogenase activity
GO:0004399 		Family Review Missing
No supported structured family review is available for InterPro:IPR022695.
trifunctional_hisd_activity histidine biosynthesis trifunctional protein family
InterPro:IPR016298
Family 		histidinol dehydrogenase activity
GO:0004399 		Family Review Missing
No supported structured family review is available for InterPro:IPR016298.

Gene-review completeness (27/30 grounded genes reviewed)

25 complete review(s) · 17 with deep research · 3 missing review · 10 reviewed but lacking deep research

Gene Review Complete Deep research
HIS1 P00498 ✓ ✓ ✓
his1 P40373 ✓ ✓ ✗
HIS2 P38635 ✓ ✓ ✓
his2 Q9P777 ✓ ✓ ✗
HIS3 P06633 ✓ ✓ ✓
his3 P36605 ✓ ✓ ✗
his4 O94303 ✓ ✓ ✗
HIS4 P00815 ✓ ✓ ✓
HIS5 P07172 ✓ ✓ ✓
his5 P40374 ✓ ✓ ✗
HIS6 P40545 ✓ ✓ ✓
his7 O59667 ✓ ✓ ✗
HIS7 P33734 ✓ ✓ ✓
hisA Q88R42 ✓ ✓ ✓
hisB Q88R45 ✓ ✓ ✓
hisC Q88P86 ✓ ✓ ✓
hisD P59400 ✓ ✓ ✓
hisE Q88D14 ✓ ✓ ✗
hisF Q88R41 ✓ ✓ ✗
hisG Q88P87 ✓ ✓ ✓
hisH Q88R44 ✓ ✓ ✓
hisI Q88D15 ✓ ✓ ✓
hisZ Q88DD7 ✓ ✓ ✓
hisJ (Bacillus subtilis) O34411 ✗ — —
hisG (Mycobacterium tuberculosis) P9WMN1 ✗ — —
PP_3157 Q88I44 ✓ 2/4 ✓
PP_5147 Q88CN3 ✓ 0/1 ✓
PA0335 (Pseudomonas aeruginosa) Q9I6F6 ✗ — —
SPAC3F10.09 Q10184 ✓ ✓ ✗
SPCC1672.01 O14059 ✓ ✓ ✗

Details

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

The reusable reaction backbone comes from GapMind, MetaCyc and SGD YeastPathways (HISTSYN-PWY), with GO and reaction identifiers checked against the local gene records. PRPP production is outside the module core; all molecular functions sit on leaf annotons. The scope covers bacteria, archaea, fungi and plants. ALIGN with YeastPathways (2026-10): the ten YeastCyc reactions map one-to-one onto the module (the two histidinol dehydrogenase half-reactions HISTOLDEHYD-RXN and HISTALDEHYD-RXN are one GO:0004399 annoton), and the seven YeastCyc catalysts (HIS1, HIS4, HIS6, HIS7, HIS3, HIS5, HIS2) are all correct; no enzymes are missing. The former separate diphosphatase and cyclohydrolase parts were merged into one part (hisie_steps) so that the standalone, bifunctional HisIE (S. pombe his7) and trifunctional HIS4 architectures could be explicit variants; histidinol dehydrogenase gained a matching monofunctional/trifunctional variant set, and IGP synthase gained a heteromeric HisH+HisF versus fused HisHF (S. cerevisiae HIS7, S. pombe his4) variant set. A PHP-family HisJ variant (S. cerevisiae HIS2, S. pombe SPCC1672.01, B. subtilis HisJ) was added for the phosphatase step. The HisC family anchor moved from PANTHER PTHR43643:SF3 to InterPro IPR005861 because the fungal enzymes sit in PANTHER PTHR42885:SF2. In both GO-CAMs every activity occurs in the cytosol; the module does not assert a compartment because the scope includes plants. GO-CAM disagreements - YeastPathways_HISTSYN-PWY types HIS7 (GLUTAMIDOTRANS-RXN) and both HIS4 histidinol dehydrogenase half-reactions only with GO:0003674 rather than GO:0000107 and GO:0004399, and has no causal edges between activities; YeastCyc gives no EC number for the two dehydrogenase half-reactions. The PomBase model (6690711d00002904) agrees with the module and additionally includes a mitochondrial histidyl-tRNA ligase (hrs1) and L-histidine transport, which are outside this module. In KT2440 the OpenScientist taxon report supports the boundary, but step 7 remains unresolved at the candidate level; its recommendation to exclude PP_5147 is not adopted because the available evidence is insufficient either to establish or to rule out that protein's histidinol-phosphatase role.

Connections

hisG_step -> hisie_steps Precedes
hisie_steps -> hisA_step Precedes
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
Variant set: ATP phosphoribosyltransferase architecture variants by enzyme architecture (Exactly One)
Short-form HisG with separate HisZ regulatory subunitProtein Complexshort_form_hisg_hisz_variant

Annotons

Short-form ATP phosphoribosyltransferase catalytic subunit
short_hisG_activity
Participant: Family: short-form HisG ATP phosphoribosyltransferase family
Family:
short-form HisG ATP phosphoribosyltransferase familyInterPro:IPR024893
Representative Members: hisG (Pseudomonas putida KT2440)UniProtKB: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

Catalytic subunit of the short-form ATPPRT architecture.

HisZ regulatory subunit of short-form ATPPRT
hisZ_regulatory_activity
Participant: Family: HisZ regulatory-subunit family
Family:
HisZ regulatory-subunit familyInterPro:IPR004517
Representative Members: hisZ (Pseudomonas putida KT2440)UniProtKB:Q88DD7

Function

ATP phosphoribosyltransferase regulatory subunit activity Non-catalytic regulation of a short-form HisG catalytic subunit.

Processes

L-histidine biosynthetic processGO:0000105

Separate regulatory subunit required by short-form HisG.

Long-form single-chain HisGReactionlong_form_hisg_variant

Fungal ATP phosphoribosyltransferases (S. cerevisiae HIS1, S. pombe his1) are long-form HisG proteins (InterPro IPR020621) that need no separate HisZ subunit.

Annotons

Long-form ATP phosphoribosyltransferase
long_hisG_activity
Participant: Family: long-form HisG ATP phosphoribosyltransferase family
Family:
long-form HisG ATP phosphoribosyltransferase familyInterPro:IPR020621
Representative Members: hisG (Mycobacterium tuberculosis)UniProtKB:P9WMN1 HIS1 (Saccharomyces cerevisiae)UniProtKB:P00498 his1 (Schizosaccharomyces pombe)UniProtKB:P40373
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

Single-chain ATPPRT architecture whose regulatory region replaces the need for a separate HisZ subunit.

Part 2: phosphoribosyl-ATP diphosphatase and phosphoribosyl-AMP cyclohydrolase
Phosphoribosyl-ATP to ProFAR (HisE and HisI reactions)Metabolic Pathwayhisie_steps

Two consecutive hydrolytic reactions: phosphoribosyl-ATP diphosphatase (HisE) releases diphosphate to give phosphoribosyl-AMP, and phosphoribosyl-AMP cyclohydrolase (HisI) opens the adenine ring to give ProFAR. The two activities are always both required, but their protein architecture varies by lineage, so the pair is modelled as one part with an explicit architecture variant set. Within every variant the diphosphatase reaction precedes the cyclohydrolase reaction.

Variant set: HisE/HisI enzyme architecture variants by enzyme architecture (Exactly One)

The HisE (phosphoribosyl-ATP pyrophosphohydrolase, InterPro IPR008179) and HisI (phosphoribosyl-AMP cyclohydrolase, Pfam PF01502) catalytic domains are the same in all three variants; only their fusion state differs. PANTHER does not separate the architectures (PSEPK standalone HisI and S. pombe bifunctional his7 are both PTHR42945:SF1), so no PANTHER family is asserted.

Separate monofunctional HisE and HisI proteinsMetabolic Pathwayseparate_hise_hisi_variant

Annotons

Phosphoribosyl-ATP diphosphatase (standalone HisE)
pr_atp_diphosphatase_activity
Participant: Family: HisE phosphoribosyl-ATP diphosphatase family
Family:
HisE phosphoribosyl-ATP diphosphatase familyInterPro:IPR008179
Representative Members: hisE (Pseudomonas putida KT2440)UniProtKB: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

Standalone diphosphatase. Gene symbols vary across taxa.

Phosphoribosyl-AMP cyclohydrolase (standalone HisI)
pr_amp_cyclohydrolase_activity
Participant: Family: phosphoribosyl-AMP cyclohydrolase family
Family:
phosphoribosyl-AMP cyclohydrolase familyInterPro:IPR026660
Representative Members: hisI (Pseudomonas putida KT2440)UniProtKB: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)

Standalone cyclohydrolase (InterPro IPR026660 is the monofunctional-protein family; the catalytic domain is Pfam PF01502).

Bifunctional HisIE protein (cyclohydrolase-diphosphatase fusion)Protein Complexbifunctional_hisie_variant

A single polypeptide carries the N-terminal HisI cyclohydrolase and C-terminal HisE diphosphatase domains; found in enterobacteria and fission yeast (S. pombe his7).

Annotons

Phosphoribosyl-ATP diphosphatase domain of bifunctional HisIE
bifunctional_hisie_diphosphatase_activity
Participant: Family: bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Family:
bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Representative Members: his7 (Schizosaccharomyces pombe)UniProtKB:O59667
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

HisE domain of the fused HisIE protein.

Phosphoribosyl-AMP cyclohydrolase domain of bifunctional HisIE
bifunctional_hisie_cyclohydrolase_activity
Participant: Family: bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Family:
bifunctional HisIE proteins (HisI and HisE domains, no HisD domain)
Representative Members: his7 (Schizosaccharomyces pombe)UniProtKB:O59667
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: ProFAR

HisI domain of the fused HisIE protein.

Trifunctional HisIE-HisD protein (HIS4-type)Protein Complextrifunctional_his4_variant

Budding-yeast HIS4 is a single polypeptide carrying the HisI cyclohydrolase, HisE diphosphatase and HisD histidinol dehydrogenase domains (PMID:379004). The same protein also fills the terminal step through the trifunctional variant of hisD_step; a lineage using this variant therefore uses trifunctional_hisd_variant at step 9 as well. S. pombe does not share this architecture: its HisIE (his7) and HisD (his2) are separate proteins.

Annotons

Phosphoribosyl-ATP diphosphatase domain of trifunctional HIS4
trifunctional_hisie_diphosphatase_activity
Participant: Family: histidine biosynthesis trifunctional protein family
Family:
histidine biosynthesis trifunctional protein familyInterPro:IPR016298
Representative Members: HIS4 (Saccharomyces cerevisiae)UniProtKB:P00815
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

HisE domain of the trifunctional HIS4 protein.

Phosphoribosyl-AMP cyclohydrolase domain of trifunctional HIS4
trifunctional_hisie_cyclohydrolase_activity
Participant: Family: histidine biosynthesis trifunctional protein family
Family:
histidine biosynthesis trifunctional protein familyInterPro:IPR016298
Representative Members: HIS4 (Saccharomyces cerevisiae)UniProtKB:P00815
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: ProFAR

HisI domain of the trifunctional HIS4 protein.

Part 3: amino-isomerase
ProFAR to PRFARReactionhisA_step

Annotons

HisA ProFAR isomerase
hisA_activity
Participant: Family: HisA ProFAR isomerase family
Family:
HisA ProFAR isomerase familyPANTHER:PTHR43090:SF2
Representative Members: hisA (Pseudomonas putida KT2440)UniProtKB:Q88R42 HIS6 (Saccharomyces cerevisiae)UniProtKB:P40545 his6 (Schizosaccharomyces pombe)UniProtKB:Q10184
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 4: imidazole-glycerol-phosphate synthase (glutamine amidotransferase)
PRFAR to imidazole-glycerol-phosphate + AICARReactionigp_synthase_step

Imidazole-glycerol-phosphate (IGP) synthase is a glutamine amidotransferase made of a cyclase (HisF) and a glutaminase / amidotransferase (HisH) unit. 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. The two units are separate subunits in most bacteria and archaea and a single fused chain in fungi.

Variant set: IGP synthase architecture variants by enzyme architecture (Exactly One)
Heterodimeric HisH-HisF IGP synthaseProtein Complexheteromeric_hish_hisf_variant

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: hisF (Pseudomonas putida KT2440)UniProtKB: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: hisH (Pseudomonas putida KT2440)UniProtKB: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.

Single-chain HisHF IGP synthase (fungal HIS7 type)Reactionfused_hishf_variant

The N-terminal glutaminase (HisH-like, TIGR01855) and C-terminal cyclase (HisF-like, TIGR00735) domains are fused in one polypeptide. Because neither half has productive activity alone, the fused protein is modelled with a single imidazoleglycerol-phosphate synthase annoton.

Annotons

Fused HisHF imidazole-glycerol-phosphate synthase
fused_hishf_activity
Participant: Family: single-chain HisHF IGP synthase family
Family:
single-chain HisHF IGP synthase familyInterPro:IPR014640
Representative Members: HIS7 (Saccharomyces cerevisiae)UniProtKB:P33734 his4 (Schizosaccharomyces pombe)UniProtKB:O94303
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

Single-chain glutamine amidotransferase/cyclase whose internal ammonia tunnel joins the two active sites.

Part 5: 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: hisB (Pseudomonas putida KT2440)UniProtKB:Q88R45 HIS3 (Saccharomyces cerevisiae)UniProtKB:P06633 his5 (Schizosaccharomyces pombe)UniProtKB:P40374
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. Fungal dehydratases are monofunctional.

Part 6: 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 familyInterPro:IPR005861
Representative Members: hisC (Pseudomonas putida KT2440)UniProtKB:Q88P86 HIS5 (Saccharomyces cerevisiae)UniProtKB:P07172 his3 (Schizosaccharomyces pombe)UniProtKB:P36605
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 fold-type I aminotransferase. In Bacillus subtilis and some related bacteria this activity is provided by a gene historically mislabelled hisH and now referred to as HisC. The family is anchored on InterPro IPR005861 because PANTHER splits bacterial (PTHR43643:SF3) and fungal (PTHR42885:SF2) HisC into different families.

Part 7: 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)

Three non-homologous implementations are modeled: IMPase-like HisN and monofunctional HAD-family enzymes (both with candidate-level PSEPK members, neither assayed in KT2440), and the PHP-family HisJ enzymes used by fungi and Bacillus. The fused enterobacterial HisB HAD domain remains a valid alternative in other lineages but is 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: PP_3157 (Pseudomonas putida KT2440)UniProtKB: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 phosphatases
Representative Members: PP_5147 (Pseudomonas putida KT2440)UniProtKB:Q88CN3 PA0335 (Pseudomonas aeruginosa)UniProtKB: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.

PHP-family HisJ implementationReactionphp_hisj_variant

Annotons

PHP-family (HisJ) histidinol-phosphate phosphatase
php_hisj_activity
Participant: Family: PHP-family HisJ histidinol-phosphatases
Family:
PHP-family HisJ histidinol-phosphatasesPANTHER:PTHR21039:SF0
Representative Members: hisJ (Bacillus subtilis)UniProtKB:O34411 HIS2 (Saccharomyces cerevisiae)UniProtKB:P38635 SPCC1672.01 (Schizosaccharomyces pombe)UniProtKB:O14059
Required Function:
histidinol-phosphatase activityGO:0004401

Function

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

Metal-dependent PHP-domain (polymerase and histidinol phosphatase domain) hydrolase; the third independent origin of this activity, used by fungi and many Firmicutes.

Part 8: terminal bifunctional dehydrogenase
L-histidinol to L-histidineReactionhisD_step

Histidinol dehydrogenase is a bifunctional NAD+-dependent enzyme that oxidises L-histidinol to L-histidine in two steps via an L-histidinal intermediate, consuming two equivalents of NAD+. The catalytic domain is a standalone protein in most lineages, including fission yeast, but is the C-terminal domain of the trifunctional HIS4 protein in budding yeast.

Variant set: Histidinol dehydrogenase architecture variants by enzyme architecture (Exactly One)

Paired with hisie_architecture_variants: the trifunctional variant here is the same polypeptide as trifunctional_his4_variant at step 2. PANTHER PTHR21256:SF2 contains both the monofunctional and the trifunctional proteins and is therefore not used to separate the variants.

Monofunctional HisDReactionmonofunctional_hisd_variant

Annotons

HisD histidinol dehydrogenase
hisD_activity
Participant: Family: monofunctional HisD histidinol dehydrogenase family
Family:
monofunctional HisD histidinol dehydrogenase familyInterPro:IPR022695
Representative Members: hisD (Pseudomonas putida KT2440)UniProtKB:P59400 his2 (Schizosaccharomyces pombe)UniProtKB:Q9P777
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.

HisD domain of trifunctional HIS4-type proteinReactiontrifunctional_hisd_variant

Annotons

Histidinol dehydrogenase domain of trifunctional HIS4
trifunctional_hisd_activity
Participant: Family: histidine biosynthesis trifunctional protein family
Family:
histidine biosynthesis trifunctional protein familyInterPro:IPR016298
Representative Members: HIS4 (Saccharomyces cerevisiae)UniProtKB:P00815
Required Function:
histidinol dehydrogenase activityGO:0004399

Function

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

C-terminal histidinol dehydrogenase domain of the trifunctional HIS4 protein; performs both oxidations.