Purine nucleotide interconversion (IMP -> AMP/GMP; purine nucleotide cycle) — ADSS1/IMPDH/AMPD disorders

Inosine monophosphate (IMP), the first complete purine nucleotide made by de novo synthesis (and by salvage), sits at the branch point from which the adenine and guanine ribonucleotides are made, and it is the hub of the purine nucleotide cycle. Toward AMP, adenylosuccinate synthetase (ADSS1 muscle / ADSS2 liver) condenses IMP with L-aspartate using GTP to form adenylosuccinate (S-AMP), which adenylosuccinate lyase (ADSL) then cleaves to AMP + fumarate. Toward GMP, IMP dehydrogenase (IMPDH1/IMPDH2) oxidises IMP to xanthosine monophosphate (XMP) with NAD+ — the committed, rate-limiting step of guanine- nucleotide synthesis — and GMP synthase (GMPS) then aminates XMP to GMP using the amide nitrogen of glutamine. Completing the cycle, AMP deaminase (AMPD1 muscle / AMPD2 broad- neuronal / AMPD3 erythrocyte) hydrolytically deaminates AMP back to IMP + ammonia; in exercising muscle the AMPD1 -> ADSS1 -> ADSL loop (the purine nucleotide cycle) buffers the adenylate energy charge and supplies fumarate (anaplerosis) and ammonia. Because GTP is required to make AMP and ATP to make GMP, these reactions also cross-regulate the two nucleotide pools. Inherited defects: ADSS1 deficiency causes a distal myopathy; IMPDH1 mutations cause retinitis pigmentosa (RP10) and IMPDH2 a neurodevelopmental dystonia (IMPDH2 is the mycophenolate/ribavirin target); AMPD1 deficiency is myoadenylate deaminase deficiency (common, often benign) and AMPD2 deficiency causes pontocerebellar hypoplasia type 9 / spastic paraplegia (SPG63).

MODULE:purine_nucleotide_interconversionDRAFTMetabolic Pathwaymodules/purine_nucleotide_interconversion.yaml
purine nucleotide biosynthetic processGO:0006164
GO:0006164
purine nucleotide biosynthetic process
The module covers purine nucleotide biosynthesis/interconversion (GO:0006164): IMP -> AMP (ADSS/ADSL), IMP -> GMP (IMPDH/GMPS) and AMP -> IMP (AMPD, purine nucleotide cycle).
Reactome:R-HSA-73817
Purine ribonucleoside monophosphate biosynthesis
Reactions follow the human Reactome purine-metabolism reactions R-HSA-111524 (ADSS), R-HSA-73794 (IMPDH), R-HSA-73792 (GMPS) and R-HSA-76590 (AMPD).
file:human/ADSS1/ADSS1-ai-review.yaml
ADSS1 gene review (human)
The IMP -> adenylosuccinate step (UniProtKB:Q8N142, GO:0004019) matches the completed human ADSS1 review.
file:human/ADSL/ADSL-ai-review.yaml
ADSL gene review (human)
The adenylosuccinate -> AMP step (UniProtKB:P30566, GO:0004018) matches the completed human ADSL review (also in the de novo purine module).
file:human/IMPDH1/IMPDH1-ai-review.yaml
IMPDH1 gene review (human)
The IMP -> XMP step (UniProtKB:P20839, GO:0003938) matches the completed human IMPDH1 review.
file:human/IMPDH2/IMPDH2-ai-review.yaml
IMPDH2 gene review (human)
The ubiquitous IMP -> XMP isozyme (UniProtKB:P12268, GO:0003938) matches the completed human IMPDH2 review.
file:human/GMPS/GMPS-ai-review.yaml
GMPS gene review (human)
The XMP -> GMP step (UniProtKB:P49915, GO:0003922) matches the completed human GMPS review.
file:human/AMPD1/AMPD1-ai-review.yaml
AMPD1 gene review (human)
The AMP -> IMP step (UniProtKB:P23109, GO:0003876) matches the completed human AMPD1 review.
file:human/AMPD2/AMPD2-ai-review.yaml
AMPD2 gene review (human)
The broad/neuronal AMP -> IMP isozyme (UniProtKB:Q01433, GO:0003876) matches the completed human AMPD2 review.
file:human/AMPD3/AMPD3-ai-review.yaml
AMPD3 gene review (human)
The erythrocyte AMP -> IMP isozyme (UniProtKB:Q01432, GO:0003876) matches the completed human AMPD3 review.
5Nodes
4Parts
0Variant Sets
0Variants
4Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:purine_nucleotide_interconversion 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.

Gene-review completeness (7/7 grounded genes reviewed)

7 complete review(s) · 0 with deep research · 0 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
ADSS1 Q8N142 ✓ ✓ ✗
AMPD1 P23109 ✓ ✓ ✗
AMPD2 Q01433 ✓ ✓ ✗
AMPD3 Q01432 ✓ ✓ ✗
GMPS P49915 ✓ ✓ ✗
IMPDH1 P20839 ✓ ✓ ✗
IMPDH2 P12268 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Purine nucleotide interconversion (IMP <-> AMP/GMP)Metabolic Pathwaypurine_nucleotide_interconversion
purine nucleotide biosynthetic processGO:0006164
Context
cytosolGO:0005829

Purine nucleotide interconversion at the IMP branch point, grounded to the human enzymes adenylosuccinate synthetase ADSS1 (UniProtKB:Q8N142, GO:0004019, EC 6.3.4.4), IMP dehydrogenase IMPDH1 (P20839) / IMPDH2 (P12268) (GO:0003938, EC 1.1.1.205), GMP synthase GMPS (P49915, GO:0003922, EC 6.3.5.2) and AMP deaminase AMPD1 (P23109) / AMPD2 (Q01433) / AMPD3 (Q01432) (GO:0003876, EC 3.5.4.6). GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector generic over the tissue isozymes and orthologs (IMPDH node carries IMPDH1+IMPDH2; AMPD node carries AMPD1/2/3). The IMP->AMP arm is completed by adenylosuccinate lyase ADSL (reviewed in the de_novo_purine_synthesis module; its GO:0004018 adenylosuccinate-lyase activity cleaves adenylosuccinate to AMP + fumarate). Upstream, IMP is produced by de novo synthesis (de_novo_purine_synthesis module, ending at ATIC) and by salvage (HPRT1, purine_salvage_and_catabolism module). The AMPD1->ADSS1->ADSL loop is the muscle purine nucleotide cycle (energy-charge buffering, fumarate anaplerosis, ammonia release). Disorders: ADSS1 -> distal myopathy; IMPDH1 -> retinitis pigmentosa 10 / LCA; IMPDH2 -> neurodevelopmental dystonia; AMPD1 -> myoadenylate deaminase deficiency; AMPD2 -> pontocerebellar hypoplasia type 9 / SPG63; AMPD3 -> benign erythrocyte AMP deaminase deficiency; GMPS has no common Mendelian disease.

Connections

impdh_step -> gmps_step Provides Input For
XMP from IMP dehydrogenase is aminated to GMP by GMP synthase.
ampd_step -> adss_step Provides Input For
AMP deaminase regenerates IMP, which adenylosuccinate synthetase re-uses toward AMP (the purine nucleotide cycle).
ampd_step -> impdh_step Provides Input For
IMP regenerated by AMP deaminase can also be routed to GMP synthesis via IMP dehydrogenase.
Part 1: IMP -> AMP (committed adenylosuccinate step)
IMP + L-aspartate + GTP to adenylosuccinate + GDP + PiReactionadss_step

Annotons

ADSS1/ADSS2: adenylosuccinate synthetase
adss_activity
Participant: Family: Adenylosuccinate synthetase family (ADSS1/ADSS2)
Family:
Adenylosuccinate synthetase family (ADSS1/ADSS2)PANTHER:PTHR11846
Representative Members: ADSS1 (human, muscle isozyme)UniProtKB:Q8N142

Function

adenylosuccinate synthase activityGO:0004019
Substrates: IMP L-aspartate GTP
Products: adenylosuccinate (N6-(1,2-dicarboxyethyl)-AMP) GDP phosphate

Locations

cytosolGO:0005829

GTP-dependent, committed first step toward AMP; adenylosuccinate lyase (ADSL) then cleaves adenylosuccinate to AMP + fumarate. ADSS1 = muscle isozyme (distal myopathy on deficiency); ADSS2 = liver/ubiquitous.

Part 2: IMP -> XMP (committed, rate-limiting GMP step)
IMP + NAD+ + H2O to XMP + NADHReactionimpdh_step

Annotons

IMPDH1/IMPDH2: IMP dehydrogenase
impdh_activity
Participant: Family: IMP dehydrogenase family (IMPDH1/IMPDH2)
Family:
IMP dehydrogenase family (IMPDH1/IMPDH2)PANTHER:PTHR11911
Representative Members: IMPDH2 (human, ubiquitous/proliferation-associated)UniProtKB:P12268 IMPDH1 (human, retina-enriched)UniProtKB:P20839

Function

IMP dehydrogenase activityGO:0003938
Substrates: IMP NAD+
Products: xanthosine 5'-monophosphate (XMP) NADH

Locations

cytosolGO:0005829

Committed, rate-limiting step of de novo GMP synthesis. IMPDH1 (retina-enriched; RP10/LCA) and IMPDH2 (ubiquitous; neurodevelopmental dystonia; mycophenolate/ ribavirin drug target) form regulated tetramers/filaments.

Part 3: XMP -> GMP (glutamine amination)
XMP + L-glutamine + ATP to GMP + L-glutamate + AMP + PPiReactiongmps_step

Annotons

GMPS: GMP synthase (glutamine-hydrolysing)
gmps_activity
Participant: Family: GMP synthase family (GMPS)
Family:
GMP synthase family (GMPS)PANTHER:PTHR11922
Representative Members: GMPS (human)UniProtKB:P49915

Function

GMP synthase (glutamine-hydrolyzing) activityGO:0003922
Substrates: XMP L-glutamine ATP
Products: GMP L-glutamate AMP + diphosphate

Locations

cytosolGO:0005829

Aminates XMP to GMP using glutamine and ATP; the final step of de novo GMP synthesis. Also has a reported USP7/p53-regulatory nuclear moonlighting role (non-core).

Part 4: AMP -> IMP (purine nucleotide cycle / regeneration)
AMP + H2O to IMP + ammoniaReactionampd_step

Annotons

AMPD1/AMPD2/AMPD3: AMP deaminase
ampd_activity
Participant: Family: AMP deaminase family (AMPD1/AMPD2/AMPD3)
Family:
AMP deaminase family (AMPD1/AMPD2/AMPD3)PANTHER:PTHR11359
Representative Members: AMPD1 (human, muscle)UniProtKB:P23109 AMPD2 (human, liver/neuronal)UniProtKB:Q01433 AMPD3 (human, erythrocyte)UniProtKB:Q01432

Function

AMP deaminase activityGO:0003876
Substrates: AMP water
Products: IMP ammonia

Locations

cytosolGO:0005829

Deaminates AMP back to IMP, closing the purine nucleotide cycle (with ADSS/ADSL) and buffering the adenylate energy charge. Isozymes AMPD1 (muscle; myoadenylate deaminase deficiency), AMPD2 (broad/neuronal; PCH9/SPG63), AMPD3 (erythrocyte; benign).