Polyamine metabolism (biosynthesis, back-conversion catabolism, and antizyme regulation)

The polyamines putrescine, spermidine and spermine are small polycationic metabolites essential for cell growth, chromatin and nucleic-acid stabilisation, ion-channel regulation and translation (spermidine is also the precursor of the eIF5A hypusine modification). Their intracellular levels are held under exceptionally tight homeostatic control by a biosynthetic arm, a catabolic/back-conversion arm and a dedicated feedback regulatory system. Biosynthesis begins with ornithine decarboxylase (ODC1), the rate-limiting, PLP-dependent enzyme that decarboxylates L-ornithine to putrescine. In parallel, the pyruvoyl-dependent S-adenosylmethionine decarboxylase (AMD1) produces decarboxylated SAM (dcSAM), the aminopropyl-group donor. Spermidine synthase (SRM) then transfers an aminopropyl group from dcSAM to putrescine to make spermidine, and spermine synthase (SMS) adds a further aminopropyl group to make spermine (each step releasing 5'-methylthioadenosine). Catabolism proceeds mainly by back-conversion: spermidine/spermine N1-acetyltransferase (SAT1) N1-acetylates spermine and spermidine using acetyl-CoA, and the peroxisomal FAD oxidase PAOX oxidises these N1-acetyl polyamines back to spermidine and putrescine (releasing H2O2 and 3-acetamidopropanal); spermine oxidase (SMOX) provides a parallel, acetylation- independent route that oxidises free spermine directly to spermidine. Overlaying all of this is the antizyme feedback loop: ornithine decarboxylase antizyme (OAZ1) — itself translated via a polyamine- stimulated +1 ribosomal frameshift — binds ODC1, inhibits it and targets it for ubiquitin-independent 26S proteasomal degradation while also suppressing polyamine uptake; antizyme inhibitor (AZIN1), a catalytically dead ODC homolog, binds and sequesters antizyme to release active ODC1. Dysregulated polyamine metabolism drives cancer and several inherited disorders (ODC1 gain-of-function Bachmann-Bupp syndrome; SMS-deficiency Snyder-Robinson syndrome; SAT1 overactivity).

MODULE:polyamine_metabolismDRAFTMetabolic Pathwaymodules/polyamine_metabolism.yaml
polyamine biosynthetic processGO:0006596 polyamine catabolic processGO:0006598
GO:0006596
polyamine biosynthetic process
ODC1, AMD1, SRM and SMS carry out polyamine biosynthesis (GO:0006596).
GO:0006598
polyamine catabolic process
SAT1, PAOX and SMOX carry out polyamine catabolism / back-conversion (GO:0006598).
file:human/ODC1/ODC1-ai-review.yaml
ODC1 gene review (human)
The ornithine->putrescine step (UniProtKB:P11926, GO:0004586) matches the completed human ODC1 review.
file:human/AMD1/AMD1-ai-review.yaml
AMD1 gene review (human)
The SAM->dcSAM aminopropyl-donor step (UniProtKB:P17707, GO:0004014) matches the completed human AMD1 review.
file:human/SRM/SRM-ai-review.yaml
SRM gene review (human)
The putrescine->spermidine step (UniProtKB:P19623, GO:0004766) matches the completed human SRM review.
file:human/SMS/SMS-ai-review.yaml
SMS gene review (human)
The spermidine->spermine step (UniProtKB:P52788, GO:0016768) matches the completed human SMS review.
file:human/SAT1/SAT1-ai-review.yaml
SAT1 gene review (human)
The polyamine N1-acetylation step (UniProtKB:P21673, GO:0004145) matches the completed human SAT1 review.
file:human/PAOX/PAOX-ai-review.yaml
PAOX gene review (human)
The N1-acetylpolyamine oxidation step (UniProtKB:Q6QHF9, GO:0052903) matches the completed human PAOX review.
file:human/SMOX/SMOX-ai-review.yaml
SMOX gene review (human)
The direct spermine->spermidine oxidation step (UniProtKB:Q9NWM0, GO:0052901) matches the completed human SMOX review.
file:human/OAZ1/OAZ1-ai-review.yaml
OAZ1 gene review (human)
The antizyme (ODC inhibitor/degradation) regulator (UniProtKB:P54368, GO:0008073) matches the completed human OAZ1 review.
file:human/AZIN1/AZIN1-ai-review.yaml
AZIN1 gene review (human)
The antizyme inhibitor / ODC activator regulator (UniProtKB:O14977, GO:0042978) matches the completed human AZIN1 review.
10Nodes
9Parts
0Variant Sets
0Variants
9Annotons
9Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:polyamine_metabolism 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 (9/9 grounded genes reviewed)

9 complete review(s) · 0 with deep research · 0 missing review · 9 reviewed but lacking deep research

Gene Review Complete Deep research
AMD1 P17707 ✓ ✓ ✗
AZIN1 O14977 ✓ ✓ ✗
OAZ1 P54368 ✓ ✓ ✗
ODC1 P11926 ✓ ✓ ✗
PAOX Q6QHF9 ✓ ✓ ✗
SAT1 P21673 ✓ ✓ ✗
SMOX Q9NWM0 ✓ ✓ ✗
SMS P52788 ✓ ✓ ✗
SRM P19623 ✓ ✓ ✗

Details

Context
cytosolGO:0005829 peroxisomal matrixGO:0005782
Polyamine metabolism (biosynthesis, catabolism, antizyme regulation)Metabolic Pathwaypolyamine_metabolism
polyamine biosynthetic processGO:0006596 polyamine catabolic processGO:0006598
Context
cytosolGO:0005829 peroxisomal matrixGO:0005782

Polyamine metabolism (GO:0006596 biosynthesis + GO:0006598 catabolism), grounded to nine completed human gene reviews. BIOSYNTHESIS (cytosol): ODC1 (P11926 PTHR11482, GO:0004586 PLP, ornithine-> putrescine, rate-limiting) + AMD1 (P17707 PTHR11570, GO:0004014 pyruvoyl, SAM->dcSAM donor) -> SRM (P19623 PTHR11558, GO:0004766, putrescine->spermidine) -> SMS (P52788 PTHR46315, GO:0016768, spermidine->spermine); each aminopropyl transfer releases MTA. CATABOLISM/back-conversion: SAT1 (P21673 PTHR10545, GO:0004145 acetyl-CoA N1-acetyltransferase, rate-limiting) -> peroxisomal PAOX (Q6QHF9 PTHR10742, GO:0052903 FAD, oxidises N1-ACETYL polyamines); plus SMOX (Q9NWM0, same PTHR10742 family, GO:0052901 FAD) which oxidises FREE spermine directly (SMOX and PAOX share the polyamine-oxidase family but differ in substrate acetylation state). REGULATION (the hallmark antizyme loop, modelled with `processes`): OAZ1 (P54368 PTHR10279, GO:0008073 ODC inhibitor activity; +1-frameshift polyamine sensor; binds ODC1, inhibits + targets it for ubiquitin-independent 26S degradation) NEGATIVELY_REGULATES ODC1; AZIN1 (O14977, catalytically-DEAD ODC homolog sharing PTHR11482 with ODC1, GO:0042978 ODC activator activity — NOT a decarboxylase) NEGATIVELY_REGULATES OAZ1 (antizyme sequestration), net-activating ODC1. Spermidine also feeds eIF5A hypusination (separate pathway). GO term ids/labels verified against the local go.db. Disorders: ODC1 gain-of-function Bachmann-Bupp syndrome; SMS-deficiency Snyder-Robinson syndrome; SAT1 overactivity; broad oncology relevance (ODC is a MYC target and DFMO drug target).

Connections

The putrescine made by ODC1 is the acceptor substrate for spermidine synthase SRM.
AMD1 supplies the dcSAM aminopropyl donor consumed by SRM.
AMD1 also supplies the dcSAM aminopropyl donor consumed by SMS.
The spermidine made by SRM is the acceptor substrate for spermine synthase SMS.
Spermine (and spermidine) are N1-acetylated by SAT1 to enter back-conversion.
Free spermine is also directly oxidised to spermidine by SMOX (acetylation-independent route).
The N1-acetyl polyamines from SAT1 are oxidised by peroxisomal PAOX, completing back-conversion.
antizyme -> ornithine_to_putrescine Negatively Regulates
OAZ1 binds ODC1, inhibits it and targets it for ubiquitin-independent proteasomal degradation.
antizyme_inhibitor -> antizyme Negatively Regulates
AZIN1 sequesters OAZ1 (antizyme), releasing active ODC1 and thereby promoting polyamine synthesis.
Part 1: putrescine synthesis (rate-limiting)
Ornithine decarboxylase (ODC1)Reactionornithine_to_putrescine

Annotons

ODC1: ornithine decarboxylase
odc1_activity
Participant: Family: ODC / group IV PLP decarboxylase family
Family:
ODC / group IV PLP decarboxylase familyPANTHER:PTHR11482
Representative Members: ODC1 (human)UniProtKB:P11926

Function

ornithine decarboxylase activityGO:0004586
Substrates: L-ornithine (PLP cofactor)
Products: putrescine CO2

Locations

cytosolGO:0005829

Decarboxylates ornithine to putrescine (rate-limiting).

Part 2: aminopropyl donor synthesis
S-adenosylmethionine decarboxylase (AMD1)Reactionsam_decarboxylation

Annotons

AMD1: adenosylmethionine decarboxylase (pyruvoyl)
amd1_activity
Participant: Family: AMD1 / S-adenosylmethionine decarboxylase family
Family:
AMD1 / S-adenosylmethionine decarboxylase familyPANTHER:PTHR11570
Representative Members: AMD1 (human)UniProtKB:P17707

Function

adenosylmethionine decarboxylase activityGO:0004014
Substrates: S-adenosyl-L-methionine (pyruvoyl cofactor; putrescine-activated)
Products: S-adenosyl 5'-methylthiopropylamine (decarboxylated SAM, dcSAM) CO2

Locations

cytosolGO:0005829

Makes decarboxylated SAM (aminopropyl donor).

Part 3: spermidine synthesis
Spermidine synthase (SRM)Reactionputrescine_to_spermidine

Annotons

SRM: spermidine synthase
srm_activity
Participant: Family: SRM / aminopropyltransferase (spermidine synthase) family
Family:
SRM / aminopropyltransferase (spermidine synthase) familyPANTHER:PTHR11558
Representative Members: SRM (human)UniProtKB:P19623

Function

spermidine synthase activityGO:0004766
Substrates: putrescine decarboxylated SAM (dcSAM)
Products: spermidine 5'-methylthioadenosine (MTA)

Locations

cytosolGO:0005829

Aminopropylates putrescine to spermidine.

Part 4: spermine synthesis
Spermine synthase (SMS)Reactionspermidine_to_spermine

Annotons

SMS: spermine synthase
sms_activity
Participant: Family: SMS / aminopropyltransferase (spermine synthase) family
Family:
SMS / aminopropyltransferase (spermine synthase) familyPANTHER:PTHR46315
Representative Members: SMS (human)UniProtKB:P52788

Function

spermine synthase activityGO:0016768
Substrates: spermidine decarboxylated SAM (dcSAM)
Products: spermine 5'-methylthioadenosine (MTA)

Locations

cytosolGO:0005829

Aminopropylates spermidine to spermine.

Part 5: polyamine acetylation (catabolism, rate-limiting)
Spermidine/spermine N1-acetyltransferase (SAT1)Reactionpolyamine_acetylation

Annotons

SAT1: diamine/spermidine-spermine N1-acetyltransferase
sat1_activity
Participant: Family: SAT1 / GNAT polyamine N-acetyltransferase family
Family:
SAT1 / GNAT polyamine N-acetyltransferase familyPANTHER:PTHR10545
Representative Members: SAT1 (human)UniProtKB:P21673

Function

diamine N-acetyltransferase activityGO:0004145
Substrates: spermine / spermidine acetyl-CoA
Products: N1-acetylspermine / N1-acetylspermidine coenzyme A

Locations

cytosolGO:0005829

N1-acetylates spermine/spermidine (commits to back-conversion).

Part 6: acetylpolyamine oxidation (back-conversion)
N1-acetylpolyamine oxidase (PAOX)Reactionacetylpolyamine_oxidation

Annotons

PAOX: N1-acetylpolyamine oxidase (FAD, peroxisomal)
paox_activity
Participant: Family: PAOX / FAD polyamine oxidase family
Family:
PAOX / FAD polyamine oxidase familyPANTHER:PTHR10742
Representative Members: PAOX (human)UniProtKB:Q6QHF9

Function

N(1)-acetylpolyamine oxidase activityGO:0052903
Substrates: N1-acetylspermine / N1-acetylspermidine O2 (FAD)
Products: spermidine / putrescine 3-acetamidopropanal + H2O2

Locations

peroxisomal matrixGO:0005782

Oxidises N1-acetyl polyamines to shorter polyamines (+ H2O2).

Part 7: direct spermine oxidation (back-conversion)
Spermine oxidase (SMOX)Reactionspermine_oxidation

Annotons

SMOX: spermine oxidase (FAD)
smox_activity
Participant: Family: SMOX / FAD polyamine oxidase family
Family:
SMOX / FAD polyamine oxidase familyPANTHER:PTHR10742
Representative Members: SMOX (human)UniProtKB:Q9NWM0

Function

spermine oxidase activityGO:0052901
Substrates: spermine (FAD) O2
Products: spermidine 3-aminopropanal + H2O2

Locations

cytosolGO:0005829

Oxidises free spermine directly to spermidine (+ H2O2).

Part 8: antizyme feedback (ODC inhibition/degradation)
Ornithine decarboxylase antizyme 1 (OAZ1)Reactionantizyme

Annotons

OAZ1: ODC antizyme (inhibitor / degradation targeting)
oaz1_activity
Participant: Family: OAZ / ornithine decarboxylase antizyme family
Family:
OAZ / ornithine decarboxylase antizyme familyPANTHER:PTHR10279
Representative Members: OAZ1 (human)UniProtKB:P54368

Processes

polyamine metabolic processGO:0006595

Locations

cytosolGO:0005829

Non-catalytic feedback regulator (GO:0008073 ODC inhibitor activity). Synthesised via a polyamine-stimulated +1 frameshift; binds ODC1, inhibits it and targets it for ubiquitin- independent 26S proteasomal degradation; also inhibits polyamine uptake.

Part 9: antizyme inhibition (ODC activation)
Antizyme inhibitor 1 (AZIN1)Reactionantizyme_inhibitor

Annotons

AZIN1: antizyme inhibitor (catalytically dead ODC homolog)
azin1_activity
Participant: Family: AZIN / antizyme inhibitor (inactive ODC homolog) family
Family:
AZIN / antizyme inhibitor (inactive ODC homolog) familyPANTHER:PTHR11482
Representative Members: AZIN1 (human)UniProtKB:O14977

Processes

polyamine metabolic processGO:0006595

Locations

cytosolGO:0005829

Catalytically DEAD ODC homolog (no ornithine decarboxylase activity); GO:0042978 ODC activator activity. Binds antizyme (OAZ1) with higher affinity than ODC, sequestering it and releasing/stabilising active ODC1 — a positive regulator of polyamine synthesis.