NAD+ consumption — sirtuin deacylation, PARP/ARTD poly- and mono-ADP-ribosylation and CD38/BST1 NAD+ glycohydrolysis, with PARG and macrodomain reversal; SIRT1-7/PARP1-4/PARP6/PARP8-12/PARP14-16/TIPARP/TNKS/TNKS2/CD38/BST1/PARG/MACROD1/MACROD2/OARD1

Besides serving as a hydride carrier in redox reactions, NAD+ is a substrate that is broken down by three classes of signalling enzymes. Each cleaves the bond between nicotinamide and ribose, releases free nicotinamide and uses the ADP-ribose moiety. The sirtuins (SIRT1-7) are NAD+-dependent protein deacylases. They transfer an acetyl group, or another acyl group such as succinyl, malonyl, glutaryl, lipoyl or a long-chain fatty acyl, from a protein lysine to the ADP-ribose of NAD+, producing nicotinamide and 2''-O-acyl-ADP-ribose. SIRT1, SIRT6 and SIRT7 act in the nucleus, SIRT2 mainly in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in mitochondria. SIRT5 is chiefly a desuccinylase, demalonylase and deglutarylase, SIRT4 a lipoamidase, and SIRT4 and SIRT6 also mono-ADP-ribosylate proteins. The PARP (ARTD) family of ADP-ribosyltransferases transfers ADP-ribose from NAD+ to protein acceptor residues. PARP1, PARP2 and the tankyrases TNKS and TNKS2 build poly(ADP-ribose) chains; DNA-break-activated PARP1, with its cofactor HPF1, is the largest NAD+ consumer after genotoxic stress. Most other PARPs (PARP3, PARP4, PARP6, PARP8, PARP10-12, PARP14-16 and TIPARP/PARP7) attach a single ADP-ribose. The ectoenzymes CD38 and BST1 (CD157) are NAD+ glycohydrolases and ADP-ribosyl cyclases. They convert NAD+ mostly to ADP-ribose and partly to the calcium-mobilising messenger cyclic ADP-ribose, which they also hydrolyse. Protein ADP-ribosylation is reversed by PAR glycohydrolase (PARG), which cleaves PAR chains, and by the macrodomain hydrolases MACROD1, MACROD2 and OARD1 (TARG1), which remove the last ADP-ribose from glutamate and aspartate residues. The nicotinamide released by all of these reactions is recycled to NAD+ by the NAMPT salvage pathway. Because the consumers share a limited NAD+ pool, strong PARP1 or CD38 activity lowers NAD+ and with it sirtuin activity, coupling DNA damage, inflammation and ageing to metabolic signalling.

MODULE:nad_consumptionDRAFTCONCRETEMetabolic Pathwaymodules/nad_consumption.yaml

NAD+ catabolic processGO:0019677

PW:0002581

nicotinamide adenine nucleotide utilization pathway

The module boundary and gene set follow the RGD Pathway Ontology record and diagram for this term. The diagram draws the NAD+ biosynthetic pathway (PW:0000219) positively affecting NAD+, and NAD+ positively affecting target deacetylation (sirtuins), target ribosylation (MAR/PAR writers, the PARPs) and cyclic ADP-ribose (Cd38, Bst1); target ribosylation positively affects target deribosylation (MAR/PAR erasers), and MAR/PAR readers are associated with target ribosylation. The RGD human gene set is APLF, BST1, CD38, CHFR, MACROD1, MACROD2, OARD1, PARG, PARP1-4, PARP6, PARP8-12, PARP14-16, RNF146, SIRT1-7, TIPARP, TNKS, TNKS2 and ZC3HAV1. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0002581.yaml).

PW:0002582

ADP-ribosylation pathway, mono and poly-ribosylation

The mono- and poly-ADP-ribosylation subpathway drawn as a node of the PW:0002581 diagram; covered by the ADP-ribosyltransferase variant and the eraser part of this module.

PW:0002583

ADP-ribosylation pathway, cyclic ribosylation

The cyclic ADP-ribosylation subpathway drawn as a node of the PW:0002581 diagram; covered by the CD38/BST1 variant.

PW:0002584

sirtuin mediated pathway

The sirtuin-mediated subpathway drawn as a node of the PW:0002581 diagram; covered by the sirtuin variant.

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

RGD PW:0002581 record text (project snapshot)

The RGD record states that NAD+ is a substrate, not only a redox cofactor, for the three consumer classes and that they compete for it.

Competition between NAD-consuming enzymes for the limited shared substrate is envisioned.

GO:0019677

NAD+ catabolic process

The curated closeMatch GO mapping for PW:0002581 (projects/RGD_PATHWAY_ONTOLOGY/data/pw_go_curated.sssom.yaml).

PMID:25043379

Family-wide analysis of poly(ADP-ribose) polymerase activity.

The family-wide PARP activity study that assigns poly- versus mono-ADP-ribosylation to each PARP, used for the ART variant split.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

Derived from the RGD Pathway Ontology record and diagram PW:0002581 (nicotinamide adenine nucleotide utilization pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route; curated GO mapping GO:0019677 NAD+ catabolic process (skos:closeMatch). The RGD diagram supplies the boundary (NAD+ in; target deacetylation, target ribosylation, cyclic ADP-ribose and target deribosylation out) and the 33-gene human set. It is modelled as two required parts and one optional part: (1) a variant set of the three NAD+-consuming enzyme classes, sirtuins, PARP/ARTD ADP-ribosyltransferases (split into poly- and mono-ADP-ribosylation) and the CD38/BST1 NAD+ glycohydrolases/ADP-ribosyl cyclases; (2) the hydrolytic reversal of protein ADP-ribosylation by PARG and the macrodomain hydrolases; and (3) an optional module_ref to the NAMPT/NMN realization of modules/nad_biosynthesis_salvage.yaml, which recycles the released nicotinamide. The three RGD subpathway terms drawn as diagram nodes (PW:0002582, PW:0002583, PW:0002584) are listed as evidence because the variants cover them. The fourth diagram link, PW:0000219 NAD+ biosynthetic pathway, is not: NAD+ synthesis is modelled in modules/nad_biosynthesis_salvage.yaml and modules/kynurenine_nad_de_novo.yaml and is only referenced here. Boundary decisions. (a) PAR readers APLF, CHFR and RNF146 are context, not participants. Each binds poly(ADP-ribose) (GO:0072572, IDA; PMID:18172500, PMID:21478859), but none consumes NAD+ or transfers or removes ADP-ribose. Their own activities (APLF histone chaperone and nuclease, CHFR and RNF146 ubiquitin ligase) act downstream in DNA repair, mitotic checkpoint control and tankyrase-directed proteolysis of AXIN. RGD itself draws the readers only as associated with target ribosylation. (b) ZC3HAV1 (PARP13, ZAP) is excluded. Its reviewed UniProt entry Q7Z2W4 states that its divergent PARP-homology domain lacks the structural requirements for NAD+ binding and is inactive. QuickGO (checked 2026-10-28) records NOT NAD+-protein mono-ADP-ribosyltransferase activity (IDA, PMID:25043379), NOT NAD+ poly-ADP-ribosyltransferase activity and NOT NAD+ binding (IMP, PMID:25635049). Its antiviral RNA-binding role is unrelated to NAD+ consumption. (c) PARP9 is in neither the RGD gene list nor the participant set, and its catalytic status is disputed. QuickGO carries both NOT GO:0003950 and NOT NAD+ binding (IMP, PMID:16061477) and positive GO:0140802 C-terminal glycine ADP-ribosyltransferase (IDA, PMID:28525742, ubiquitin ADP-ribosylation by the DTX3L-PARP9 heterodimer) and GO:0003950 (IDA, PMID:23230272). PMID:27796300 found that PARP9 does not ADP-ribosylate STAT1 and instead suppresses PARP14. This is recorded as a knowledge gap. (d) GO usage of GO:0019677. In human GOA the term is carried only by NAD+-degrading enzymes: SARM1 (IDA, many papers), NUDT12 (IDA), NUDT17 (IBA), plus IEA rows on NNMT and PARP14 (GO_REF:0000107). No sirtuin or PARP carries it, because GO describes their process as protein deacylation or ADP-ribosylation, with NAD+ as cosubstrate. GO:0019677 is therefore kept as the module-level concept (the closeMatch) and is not put on the sirtuin or PARP annotons. It is put on the CD38 and BST1 annotons, because their NAD+ glycohydrolase chemistry (NAD+ to ADP-ribose or cADPR plus nicotinamide) is the same as that of SARM1, whose GO:0019677 annotation rests on IDA. Neither CD38 nor BST1 carries GO:0019677 in GOA; this is a possible curation gap, not asserted here as a GOA annotation. The PARP14 IEA row looks like an over-propagated orthology transfer and is a candidate for upstream review. (e) Molecular functions come from each protein's experimental GO annotations in QuickGO (checked 2026-10-28), cross-checked against the Rhea xrefs of the GO terms and the cached abstracts: SIRT1, SIRT2, SIRT3, SIRT6 and SIRT7 GO:0034979 (EXP/IDA; RHEA:43636); SIRT5 GO:0036055 (IDA; RHEA:47668; demalonylase GO:0036054 and deglutarylase GO:0061697 in prose); SIRT4 GO:0106419 (EXP/IDA; RHEA:63640) and GO:0140803 (EXP; RHEA:56612); SIRT6 GO:0140804 (EXP; RHEA:58220); PARP1 GO:0140805 (EXP/IDA; RHEA:58232) and GO:0003950 (EXP/IDA); PARP2, TNKS and TNKS2 GO:0003950 (IDA/EXP); PARP3, PARP4, PARP8, PARP11, PARP12, PARP15 and TIPARP GO:1990404 (IDA); PARP6 GO:0140803 (IDA); PARP10, PARP14 and PARP16 GO:0140807 (EXP/IDA; RHEA:58224); CD38 and BST1 GO:0061809 (EXP/IDA; RHEA:38611, RHEA:38615, plus NAD+ hydrolysis RHEA:16301); PARG GO:0004649 (EXP/IDA; RHEA:52216); MACROD1, MACROD2 and OARD1 GO:0140293 (IDA; RHEA:58248). PAR chain elongation (EC 2.4.2.30) has no Rhea reaction, so the PAR annotons carry the EC equation in prose. Most PARP mono-ARTs (PARP3, PARP4, PARP6, PARP8, PARP10, PARP11, PARP12, PARP14, PARP15, PARP16, TIPARP) also carry GO:0003950 poly-ADP-ribosyltransferase activity in GOA, by IBA and in some cases IDA/IMP. That conflicts with the family-wide product assignment (PMID:25043379), which found that most PARPs make MAR, and with the substrate-assisted mechanism that prevents PARP10-type enzymes from polymerising (PMID:18851833). These rows are candidates for IBA and upstream review, and GO:0003950 is not used for them here. Also not adopted: SIRT7 protein methyltransferase activity (GO:0008276, IDA; also an activity in GO-CAM gomodel:63c0ac2b00001853). It is unexpected for a sirtuin and is flagged for review. (f) Outside the RGD gene list and the module: the serine-ADP-ribose hydrolase ADPRS (ARH3), which removes the HPF1-dependent serine mono-ADP-ribose that PARG leaves; the NUDIX ADP-ribose pyrophosphatases (NUDT5, NUDT9) that clear free ADP-ribose; the NAD+ hydrolase SARM1; the ecto-ARTs ART1-5; and NNMT, which methylates the nicotinamide product. The ADPRS omission means the reversal part as drawn by RGD is incomplete for serine-linked marks. The PARP1 cofactor HPF1 is described in the PARP1 annoton but is not a participant. Downstream signalling by cADPR (ryanodine receptors) and NAADP (two-pore channels) is out of scope. (g) GO-CAM: gocams/index.tsv (checked 2026-10-28) has production models for 12 of the 33 genes. The project's best-overlap model gomodel:627d95ee00002067 is linked at module level and on the PARP1 and PARP2 annotons, and further models are linked on the SIRT1, SIRT2, SIRT3, SIRT6, SIRT7, PARP1, PARP2, PARP12 and PARP16 annotons. Possible GO-CAM issue: in gomodel:696022cd00000603 (Regulation of the TCA cycle by SIRT3) the SIRT3 deacetylase activity is part of GO:0008053 mitochondrial fusion, which does not match the model title. Gene reviews exist for PARP1, SIRT1, SIRT2, SIRT5 and TNKS; the other members have none. Publications cited are abstract-only in the cache except PMID:22076378, PMID:25525879, PMID:27568560, PMID:28190768, PMID:23481255, PMID:23275542, PMID:27796300, PMID:30104678 and PMID:34314702.

16Nodes

3Parts

5Variant Sets

12Variants

31Annotons

2Connections

Derived QC

Recommended-field compliance

80.0% recommended fields populated

knowledge_gaps[0].provenance[0] · reference_section_type (0/1)
knowledge_gaps[0].provenance[1] · reference_section_type (0/1)
knowledge_gaps[1].provenance[0] · reference_section_type (0/1)

Module deep research

✗ none found

No MODULE:nad_consumption 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.

Function consistency and core coverage

6 gene-function check(s) reflected in core functions · 0 conflict(s) · 25 evidence or coverage gap(s) (31 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.

Annoton	Participant	Function	Assessment
sirt1_deacetylase	SIRT1 UniProtKB:Q96EB6 Gene	NAD-dependent protein lysine deacetylase activity GO:0034979	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sirt2_deacetylase	SIRT2 UniProtKB:Q8IXJ6 Gene	NAD-dependent protein lysine deacetylase activity GO:0034979	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sirt3_deacetylase	SIRT3 UniProtKB:Q9NTG7 Gene	NAD-dependent protein lysine deacetylase activity GO:0034979	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sirt6_deacetylase	SIRT6 UniProtKB:Q8N6T7 Gene	NAD-dependent protein lysine deacetylase activity GO:0034979	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sirt7_deacetylase	SIRT7 UniProtKB:Q9NRC8 Gene	NAD-dependent protein lysine deacetylase activity GO:0034979	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sirt5_desuccinylase	SIRT5 UniProtKB:Q9NXA8 Gene	protein-succinyllysine desuccinylase activity GO:0036055	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
sirt4_lipoamidase	SIRT4 UniProtKB:Q9Y6E7 Gene	NAD-dependent protein lipoamidase activity GO:0106419	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sirt6_mart	SIRT6 UniProtKB:Q8N6T7 Gene	NAD+-protein-lysine ADP-ribosyltransferase activity GO:0140804	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
sirt4_mart	SIRT4 UniProtKB:Q9Y6E7 Gene	NAD+-protein-cysteine ADP-ribosyltransferase activity GO:0140803	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp1_ser_initiation	PARP1 UniProtKB:P09874 Gene	NAD+-protein-serine ADP-ribosyltransferase activity GO:0140805	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
parp1_par	PARP1 UniProtKB:P09874 Gene	NAD+ poly-ADP-ribosyltransferase activity GO:0003950	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
parp2_par	PARP2 UniProtKB:Q9UGN5 Gene	NAD+ poly-ADP-ribosyltransferase activity GO:0003950	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
tnks_par	TNKS UniProtKB:O95271 Gene	NAD+ poly-ADP-ribosyltransferase activity GO:0003950	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tnks2_par	TNKS2 UniProtKB:Q9H2K2 Gene	NAD+ poly-ADP-ribosyltransferase activity GO:0003950	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp3_mart	PARP3 UniProtKB:Q9Y6F1 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp4_mart	PARP4 UniProtKB:Q9UKK3 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp6_mart	PARP6 UniProtKB:Q2NL67 Gene	NAD+-protein-cysteine ADP-ribosyltransferase activity GO:0140803	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp8_mart	PARP8 UniProtKB:Q8N3A8 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp10_mart	PARP10 UniProtKB:Q53GL7 Gene	NAD+-protein-glutamate ADP-ribosyltransferase activity GO:0140807	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp11_mart	PARP11 UniProtKB:Q9NR21 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp12_mart	PARP12 UniProtKB:Q9H0J9 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp14_mart	PARP14 UniProtKB:Q460N5 Gene	NAD+-protein-glutamate ADP-ribosyltransferase activity GO:0140807	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp15_mart	PARP15 UniProtKB:Q460N3 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parp16_mart	PARP16 UniProtKB:Q8N5Y8 Gene	NAD+-protein-glutamate ADP-ribosyltransferase activity GO:0140807	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
tiparp_mart	TIPARP UniProtKB:Q7Z3E1 Gene	NAD+-protein mono-ADP-ribosyltransferase activity GO:1990404	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cd38_cyclase	CD38 UniProtKB:P28907 Gene	NAD+ nucleosidase activity, cyclic ADP-ribose generating GO:0061809	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bst1_cyclase	BST1 UniProtKB:Q10588 Gene	NAD+ nucleosidase activity, cyclic ADP-ribose generating GO:0061809	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
parg_glycohydrolase	PARG UniProtKB:Q86W56 Gene	poly(ADP-ribose) glycohydrolase activity GO:0004649	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
macrod1_hydrolase	MACROD1 UniProtKB:Q9BQ69 Gene	ADP-ribosylglutamate-[protein] hydrolase activity GO:0140293	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
macrod2_hydrolase	MACROD2 UniProtKB:A1Z1Q3 Gene	ADP-ribosylglutamate-[protein] hydrolase activity GO:0140293	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
oard1_hydrolase	OARD1 UniProtKB:Q9Y530 Gene	ADP-ribosylglutamate-[protein] hydrolase activity GO:0140293	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.

Gene-review completeness (5/28 grounded genes reviewed)

3 complete review(s) · 4 with deep research · 23 missing review · 1 reviewed but lacking deep research

Gene	Review	Complete	Deep research
MACROD2 A1Z1Q3	✗	—	—
CD38 P28907	✗	—	—
PARP1 P09874	✓	✓	✗
BST1 Q10588	✗	—	—
PARP6 Q2NL67	✗	—	—
PARP15 Q460N3	✗	—	—
PARP14 Q460N5	✗	—	—
PARP10 Q53GL7	✗	—	—
TIPARP Q7Z3E1	✗	—	—
PARG Q86W56	✗	—	—
PARP8 Q8N3A8	✗	—	—
PARP16 Q8N5Y8	✗	—	—
SIRT6 Q8N6T7	✗	—	—
MACROD1 Q9BQ69	✗	—	—
PARP12 Q9H0J9	✗	—	—
TNKS2 Q9H2K2	✗	—	—
PARP11 Q9NR21	✗	—	—
SIRT7 Q9NRC8	✗	—	—
SIRT3 Q9NTG7	✗	—	—
PARP2 Q9UGN5	✗	—	—
PARP4 Q9UKK3	✗	—	—
OARD1 Q9Y530	✗	—	—
SIRT4 Q9Y6E7	✗	—	—
PARP3 Q9Y6F1	✗	—	—
SIRT1 Q96EB6	✓	364/380	✓
SIRT2 Q8IXJ6	✓	188/193	✓
SIRT5 Q9NXA8	✓	✓	✓
TNKS O95271	✓	✓	✓

Details

Context

Homo sapiensNCBITaxon:9606

NAD+ consumption by sirtuins, ADP-ribosyltransferases and NAD+ glycohydrolasesMetabolic Pathwaynad_consumption

Sirtuins, PARP-family ADP-ribosyltransferases and the CD38/BST1 NAD+ glycohydrolases each cleave NAD+ and release nicotinamide; the protein ADP-ribosylation made by PARPs is reversed by PARG and the macrodomain hydrolases, and the nicotinamide is salvaged to NAD+ by NAMPT.

NAD+ catabolic processGO:0019677

Context

Homo sapiensNCBITaxon:9606

Connections

adp_ribosyltransferase_nad_consumption -> adp_ribose_removal Provides Input For

Poly- and mono-ADP-ribosylated proteins made by the PARPs are the substrates of PARG and the macrodomain hydrolases.

nad_consuming_reactions -> nicotinamide_salvage_to_nad Provides Input For

Nicotinamide (CHEBI:17154), the common product of every consumer reaction, is the NAMPT substrate in the referenced salvage route.

Part 1: NAD+ cleavage with nicotinamide release by a consumer enzyme

NAD+-consuming enzyme classesMetabolic Pathwaynad_consuming_reactions

Three enzyme classes use NAD+ as a substrate rather than as a redox cofactor. Each cleaves the nicotinamide-ribosyl bond, releases nicotinamide and destroys the NAD+ molecule.

NAD+ catabolic processGO:0019677

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

The RGD record defines the three NAD+-utilisation routes modelled as the variants.

There are three pathways of NAD utilization: the sirtuin mediated pathway and the ADP ribosylation pathways - mono and poly-ribosylation, and cyclic ribosylation.

Variant set: NAD+-consuming enzyme class by enzyme class (sirtuin deacylase, ADP-ribosyltransferase, NAD+ glycohydrolase/cyclase) (One Or More)

Sirtuin NAD+-dependent deacylation and ADP-ribosylationMolecular Functionsirtuin_nad_consumption

Class III protein deacylases (sirtuins 1-7) share a conserved NAD+-binding catalytic core. They cleave the nicotinamide-ribosyl bond of NAD+ and transfer the protein acyl group to the ADP-ribose, so every deacylation consumes one NAD+ and yields nicotinamide and 2''-O-acyl-ADP-ribose. Nicotinamide is a non-competitive feedback inhibitor, which makes sirtuin activity sensitive to the NAD+/nicotinamide ratio.

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

The RGD record defines the sirtuin route and names nicotinamide as its inhibitory product.

NAM, the product of the reaction, binds noncompetitively to sirtuins and inhibits them.

Variant set: Sirtuin reaction by acyl group removed or ADP-ribose transferred (One Or More)

NAD+-dependent lysine deacetylation (SIRT1, SIRT2, SIRT3, SIRT6, SIRT7)Reactionsirtuin_deacetylation

Removal of an acetyl group from a protein lysine with NAD+ as cosubstrate. The ADP-ribose of NAD+ accepts the acetyl group, so each deacetylation consumes one NAD+ and releases nicotinamide and 2''-O-acetyl-ADP-ribose.

Annotons

SIRT1 NAD-dependent protein lysine deacetylase activity

sirt1_deacetylase

Participant: Gene Product: SIRT1

Gene Product:

SIRT1UniProtKB:Q96EB6

Function

NAD-dependent protein lysine deacetylase activityGO:0034979

Substrates: N6-acetyl-L-lysyl-[protein]CHEBI:61930 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-acetyl-ADP-D-riboseCHEBI:83767 nicotinamideCHEBI:17154

Processes

protein deacetylationGO:0006476

Locations

nucleusGO:0005634

Nuclear sirtuin and the best-characterised NAD+-dependent deacetylase; deacetylates histones and many transcription factors and coregulators, including p53 at Lys382.

PMID:11672523

Human SIRT1 is an NAD-dependent deacetylase of p53.

binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue

SIRT2 NAD-dependent protein lysine deacetylase activity

sirt2_deacetylase

Participant: Gene Product: SIRT2

Gene Product:

SIRT2UniProtKB:Q8IXJ6

Function

NAD-dependent protein lysine deacetylase activityGO:0034979

Substrates: N6-acetyl-L-lysyl-[protein]CHEBI:61930 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-acetyl-ADP-D-riboseCHEBI:83767 nicotinamideCHEBI:17154

Processes

protein deacetylationGO:0006476

Locations

cytosolGO:0005829

Predominantly cytoplasmic sirtuin that deacetylates alpha-tubulin and, at the G2/M transition, histone H4K16; it also removes long-chain fatty acyl groups (demyristoylase/depalmitoylase activity, retained in the SIRT2 gene review).

PMID:16648462

SIRT2 deacetylates histone H4K16Ac in vitro and in vivo.

SirT2 and its yeast counterpart Hst2 have a strong preference for histone H4K16Ac in their deacetylation activity in vitro and in vivo

SIRT3 NAD-dependent protein lysine deacetylase activity

sirt3_deacetylase

Participant: Gene Product: SIRT3

Gene Product:

SIRT3UniProtKB:Q9NTG7

Function

NAD-dependent protein lysine deacetylase activityGO:0034979

Substrates: N6-acetyl-L-lysyl-[protein]CHEBI:61930 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-acetyl-ADP-D-riboseCHEBI:83767 nicotinamideCHEBI:17154

Processes

protein deacetylationGO:0006476

Locations

mitochondrial matrixGO:0005759

Major deacetylase of the mitochondrial matrix; activates glutamate dehydrogenase, isocitrate dehydrogenase 2 and other metabolic enzymes by deacetylation.

PMID:18680753

SIRT3 deacetylates and activates mitochondrial matrix glutamate dehydrogenase.

We show that Sirt3 can deacetylate and thereby activate a central metabolic regulator in the mitochondrial matrix, glutamate dehydrogenase

SIRT6 NAD-dependent protein lysine deacetylase activity

sirt6_deacetylase

Participant: Gene Product: SIRT6

Gene Product:

SIRT6UniProtKB:Q8N6T7

Function

NAD-dependent protein lysine deacetylase activityGO:0034979

Substrates: N6-acetyl-L-lysyl-[protein]CHEBI:61930 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-acetyl-ADP-D-riboseCHEBI:83767 nicotinamideCHEBI:17154

Processes

protein deacetylationGO:0006476

Locations

chromatinGO:0000785

Chromatin-bound sirtuin that deacetylates histone H3K9, H3K18 and H3K56 and non-histone targets, and removes long-chain fatty acyl groups; its separate mono-ADP-ribosyltransferase activity is a variant below.

PMID:27568560

SIRT6 has both deacetylase and mono-ADP-ribosyltransferase activity.

SIRT6 catalyzes both deacetylation and mono-ADP ribosylation

SIRT7 NAD-dependent protein lysine deacetylase activity

sirt7_deacetylase

Participant: Gene Product: SIRT7

Gene Product:

SIRT7UniProtKB:Q9NRC8

Function

NAD-dependent protein lysine deacetylase activityGO:0034979

Substrates: N6-acetyl-L-lysyl-[protein]CHEBI:61930 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-acetyl-ADP-D-riboseCHEBI:83767 nicotinamideCHEBI:17154

Processes

protein deacetylationGO:0006476

Locations

nucleolusGO:0005730

Nucleolar sirtuin; deacetylates H3K18 and the RNA polymerase I subunit PAF53, coupling rDNA transcription to stress. SIRT7 also carries desuccinylase and deglutarylase annotations (IDA).

PMID:24207024

SIRT7 deacetylates the Pol I subunit PAF53 at Lys373.

Acetylation of PAF53 at lysine 373 by CBP and deacetylation by SIRT7 modulate the association of Pol I with DNA

NAD+-dependent removal of other lysine acyl groups (SIRT5 desuccinylation, SIRT4 delipoylation)Reactionsirtuin_other_deacylation

Some sirtuins prefer acyl groups other than acetyl. The chemistry is the same: the acyl group is transferred to the ADP-ribose of NAD+, giving nicotinamide and 2''-O-acyl-ADP-ribose.

Annotons

SIRT5 protein-succinyllysine desuccinylase activity

sirt5_desuccinylase

Participant: Gene Product: SIRT5

Gene Product:

SIRT5UniProtKB:Q9NXA8

Function

protein-succinyllysine desuccinylase activityGO:0036055 Desuccinylation is modelled as the representative reaction; SIRT5 equally demalonylates and deglutarylates (GO:0036054 and GO:0061697, both core in the SIRT5 gene review).

Substrates: N6-succinyl-L-lysyl-[protein]CHEBI:87830 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-succinyl-ADP-D-riboseCHEBI:87832 nicotinamideCHEBI:17154

Processes

protein desuccinylationGO:0036048

Locations

mitochondrial matrixGO:0005759

Mitochondrial sirtuin with weak deacetylase but efficient desuccinylase, demalonylase and deglutarylase activity, set by Tyr102 and Arg105 in its acyl pocket.

PMID:22076378

SIRT5 is an efficient lysine desuccinylase and demalonylase.

is an efficient protein lysine desuccinylase and demalonylase in vitro

PMID:22076378

The sirtuin mechanism transfers the acyl group to ADP-ribose, giving O-acyl-ADP-ribose.

O-malonyl-ADPR (O-Ma-ADPR) or O-succinyl-ADPR (O-Su-ADPR) should be produced

SIRT4 NAD-dependent protein lipoamidase activity

sirt4_lipoamidase

Participant: Gene Product: SIRT4

Gene Product:

SIRT4UniProtKB:Q9Y6E7

Function

NAD-dependent protein lipoamidase activityGO:0106419

Substrates: N6-lipoyl-L-lysyl-[protein]CHEBI:83099 NAD+CHEBI:57540 waterCHEBI:15377

Products: L-lysyl-[protein]CHEBI:29969 2''-O-lipoyl-ADP-D-riboseCHEBI:189572 nicotinamideCHEBI:17154

Locations

mitochondrial matrixGO:0005759

Mitochondrial sirtuin with no detectable deacetylase activity (NOT GO:0034979, IDA) that removes lipoyl groups from the DLAT E2 subunit of the pyruvate dehydrogenase complex, lowering PDH activity.

PMID:25525879

SIRT4 delipoylates DLAT and inhibits the pyruvate dehydrogenase complex.

glutamine stimulation induces endogenous SIRT4 lipoamidase activity, triggering a reduction in both DLAT lipoyl levels and PDH activity

Sirtuin mono-ADP-ribosyltransferase activity (SIRT4, SIRT6)Reactionsirtuin_mono_adp_ribosylation

SIRT4 and SIRT6 also transfer the whole ADP-ribose of NAD+ to a protein acceptor, releasing nicotinamide. The physiological weight of this activity, relative to their deacylase activities, is less certain than for the PARPs.

Annotons

SIRT6 NAD+-protein-lysine ADP-ribosyltransferase activity

sirt6_mart

Participant: Gene Product: SIRT6

Gene Product:

SIRT6UniProtKB:Q8N6T7

Function

NAD+-protein-lysine ADP-ribosyltransferase activityGO:0140804

Substrates: L-lysyl-[protein]CHEBI:29969 NAD+CHEBI:57540

Products: N6-(ADP-D-ribosyl)-L-lysyl-[protein]CHEBI:142515 nicotinamideCHEBI:17154 H+CHEBI:15378

Locations

site of DNA damageGO:0090734

Under oxidative stress SIRT6 mono-ADP-ribosylates PARP1 on Lys521, stimulating PARP1 poly-ADP-ribosylation at DNA double-strand breaks.

PMID:27568560

SIRT6 mono-ADP-ribosylates PARP1 Lys521.

SIRT6-mediated mono-ADP ribosylation of PARP1 on lysine 521 activates PARP1 poly-ADP ribosylation activity

SIRT4 NAD+-protein-cysteine ADP-ribosyltransferase activity

sirt4_mart

Participant: Gene Product: SIRT4

Gene Product:

SIRT4UniProtKB:Q9Y6E7

Function

NAD+-protein-cysteine ADP-ribosyltransferase activityGO:0140803

Substrates: L-cysteinyl-[protein]CHEBI:29950 NAD+CHEBI:57540

Products: S-(ADP-D-ribosyl)-L-cysteinyl-[protein]CHEBI:140607 nicotinamideCHEBI:17154 H+CHEBI:15378

Locations

mitochondrial matrixGO:0005759

SIRT4 ADP-ribosylates glutamate dehydrogenase and model acceptors, inhibiting GDH; the cysteine acceptor follows the GOA EXP annotation from the same study.

PMID:17715127

SIRT4 is an ADP-ribosyltransferase rather than a deacetylase.

SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin

ADP-ribosyltransferase (PARP/ARTD) transfer of ADP-ribose from NAD+ to proteinsMolecular Functionadp_ribosyltransferase_nad_consumption

Diphtheria-toxin-like ADP-ribosyltransferases (the PARP/ARTD family) cleave NAD+ and transfer its ADP-ribose to a protein acceptor (or to DNA ends), releasing nicotinamide. They divide by product into poly-ADP-ribose polymerases and mono-ADP-ribosyltransferases.

PMID:25043379

PAR versus MAR products were assigned experimentally across the family; most PARPs make MAR, which sets this variant split.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

Variant set: ADP-ribosylation product by poly- versus mono-ADP-ribosylation (One Or More)

Poly-ADP-ribose polymerases (PARP1, PARP2, TNKS, TNKS2)Molecular Functionpoly_adp_ribosylation

The few PARPs that keep the catalytic glutamate of the H-Y-E triad build ADP-ribose chains of up to about 200 units on an initiating ADP-ribose, consuming one NAD+ per unit.

Annotons

PARP1 NAD+-protein-serine ADP-ribosyltransferase activity (with HPF1)

parp1_ser_initiation

Participant: Gene Product: PARP1

Gene Product:

PARP1UniProtKB:P09874

Function

NAD+-protein-serine ADP-ribosyltransferase activityGO:0140805

Substrates: L-seryl-[protein]CHEBI:29999 NAD+CHEBI:57540

Products: O-(ADP-D-ribosyl)-L-seryl-[protein]CHEBI:142556 nicotinamideCHEBI:17154 H+CHEBI:15378

Locations

site of DNA damageGO:0090734

At DNA breaks, PARP1 bound to its cofactor HPF1 attaches the first ADP-ribose to serine residues of histones and of PARP1 itself; this is the main initiation site of DNA damage-induced ADP-ribosylation.

PMID:28190768

Serine ADP-ribosylation by PARP1 depends on HPF1.

demonstrating that PARP-1 auto-ADPr on serine is also dependent on HPF1

PARP1 NAD+ poly-ADP-ribosyltransferase activity

parp1_par

Participant: Gene Product: PARP1

Gene Product:

PARP1UniProtKB:P09874

Function

NAD+ poly-ADP-ribosyltransferase activityGO:0003950 NAD(+) + (ADP-D-ribosyl)n-acceptor = nicotinamide + (ADP-D-ribosyl)n+1-acceptor + H(+) (EC 2.4.2.30). Rhea has no reaction for chain elongation; the polymer is represented by CHEBI:142512.

Substrates: NAD+CHEBI:57540

Products: poly(ADP-ribose)CHEBI:142512 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

protein poly-ADP-ribosylationGO:0070212

Locations

site of DNA damageGO:0090734

DNA-break-activated PARP1 elongates and branches poly(ADP-ribose) chains; at maximal activation it can deplete cellular NAD+ by most of its pool, which is the basis of PARP1-SIRT1 competition for NAD+.

PMID:7852410

The catalytic Glu988 is required for poly-ADP-ribose elongation by PARP1.

Glu988 may function in polymer elongation similarly to the toxins' active site glutamate

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

RGD records the scale of PARP1-driven NAD+ depletion.

The decrease in NAD concentration can reach 80% with maximal PARP1 activation.

PARP2 NAD+ poly-ADP-ribosyltransferase activity

parp2_par

Participant: Gene Product: PARP2

Gene Product:

PARP2UniProtKB:Q9UGN5

Function

Substrates: NAD+CHEBI:57540

Products: poly(ADP-ribose)CHEBI:142512 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

protein poly-ADP-ribosylationGO:0070212

Locations

site of DNA damageGO:0090734

DNA-damage-activated PARP2 is stimulated by PARP1-made PAR and synthesises branched chains; with HPF1 it also initiates on serine (GO:0140805, IDA).

PMID:30104678

PARP2 synthesises branched PAR after activation by PAR.

PARP2 is preferentially activated by PAR and subsequently catalyzes branched PAR chain synthesis

Tankyrase-1 (TNKS) NAD+ poly-ADP-ribosyltransferase activity

tnks_par

Participant: Gene Product: TNKS

Gene Product:

TNKSUniProtKB:O95271

Function

Substrates: NAD+CHEBI:57540

Products: poly(ADP-ribose)CHEBI:142512 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

protein poly-ADP-ribosylationGO:0070212

Locations

cytosolGO:0005829

Ankyrin-repeat PARP that poly-ADP-ribosylates TRF1, AXIN and itself; the PAR it adds is read by RNF146 and directs targets to proteasomal degradation.

PMID:9822378

Recombinant tankyrase has PARP activity toward TRF1 and itself.

Recombinant tankyrase was found to have PARP activity in vitro, with both TRF1 and tankyrase functioning as acceptors for adenosine diphosphate (ADP)-ribosylation

Tankyrase-2 (TNKS2) NAD+ poly-ADP-ribosyltransferase activity

tnks2_par

Participant: Gene Product: TNKS2

Gene Product:

TNKS2UniProtKB:Q9H2K2

Function

Substrates: NAD+CHEBI:57540

Products: poly(ADP-ribose)CHEBI:142512 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

protein poly-ADP-ribosylationGO:0070212

Locations

cytosolGO:0005829

Tankyrase-1 paralogue with the same substrate range and partial redundancy.

PMID:11739745

Recombinant tankyrase 2 poly-ADP-ribosylates itself and TRF1.

Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1

Mono-ADP-ribosyltransferases (PARP3, PARP4, PARP6, PARP8, PARP10-12, PARP14-16, TIPARP)Molecular Functionmono_adp_ribosylation

Most PARPs lack the catalytic glutamate and transfer a single ADP-ribose to an acceptor residue (glutamate, aspartate, cysteine, lysine or serine), consuming one NAD+ per modification.

Annotons

PARP3 NAD+-protein mono-ADP-ribosyltransferase activity

parp3_mart

Participant: Gene Product: PARP3

Gene Product:

PARP3UniProtKB:Q9Y6F1

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Locations

nucleusGO:0005634

DNA-break-associated mono-ADP-ribosyltransferase that modifies histone H1 and itself and, with PARP1, acts in double-strand break repair.

PMID:20064938

PARP3 is a mono-ADP-ribosylase, unlike PARP1 and PARP2.

PARP-3 is not activated upon binding to DNA and is a mono-ADP-ribosylase, in contrast to PARP-1 and PARP-2

PARP4 NAD+-protein mono-ADP-ribosyltransferase activity

parp4_mart

Participant: Gene Product: PARP4

Gene Product:

PARP4UniProtKB:Q9UKK3

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Locations

cytosolGO:0005829

Vault-associated PARP (VPARP); mono-ADP-ribosyltransferase activity shown in the family-wide assay (IDA). Its physiological substrates are poorly defined.

PMID:25043379

Family-wide assay of PARP products, the IDA source for PARP4 GO:1990404.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP6 NAD+-protein-cysteine ADP-ribosyltransferase activity

parp6_mart

Participant: Gene Product: PARP6

Gene Product:

PARP6UniProtKB:Q2NL67

Function

NAD+-protein-cysteine ADP-ribosyltransferase activityGO:0140803

Substrates: L-cysteinyl-[protein]CHEBI:29950 NAD+CHEBI:57540

Products: S-(ADP-D-ribosyl)-L-cysteinyl-[protein]CHEBI:140607 nicotinamideCHEBI:17154 H+CHEBI:15378

Mono-ADP-ribosylates cysteine (and aspartate) residues in the family-wide automodification assay (IDA).

PMID:25043379

Family-wide assay identifying cysteine as an ADP-ribose acceptor, the IDA source for PARP6 GO:0140803.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP8 NAD+-protein mono-ADP-ribosyltransferase activity

parp8_mart

Participant: Gene Product: PARP8

Gene Product:

PARP8UniProtKB:Q8N3A8

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

PARP6 paralogue; mono-ADP-ribosyltransferase activity with cysteine acceptors (GO:0140803, EXP).

PMID:25043379

Family-wide assay, the IDA/EXP source for PARP8 mono-ADP-ribosyltransferase activity.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP10 NAD+-protein-glutamate ADP-ribosyltransferase activity

parp10_mart

Participant: Gene Product: PARP10

Gene Product:

PARP10UniProtKB:Q53GL7

Function

NAD+-protein-glutamate ADP-ribosyltransferase activityGO:0140807

Substrates: L-glutamyl-[protein]CHEBI:29973 NAD+CHEBI:57540

Products: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 nicotinamideCHEBI:17154

Prototype mono-ART of the family: lacking the catalytic glutamate, it uses substrate-assisted catalysis to mono-ADP-ribosylate acidic residues (for example of GSK3B), a modification reversed by MACROD1, MACROD2 and OARD1.

PMID:18851833

PARP10 is a transferase rather than a polymerase.

PARP10, in contrast to PARP1, lacks the catalytic glutamate and has transferase rather than polymerase activity

PMID:18851833

PARP10 modifies acidic residues.

PARP10 also modifies acidic residues

PARP11 NAD+-protein mono-ADP-ribosyltransferase activity

parp11_mart

Participant: Gene Product: PARP11

Gene Product:

PARP11UniProtKB:Q9NR21

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Mono-ADP-ribosyltransferase with glutamate, aspartate, lysine and cysteine acceptors in the family-wide assay (EXP).

PMID:25043379

Family-wide assay, the IDA/EXP source for PARP11 mono-ADP-ribosyltransferase activity.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP12 NAD+-protein mono-ADP-ribosyltransferase activity

parp12_mart

Participant: Gene Product: PARP12

Gene Product:

PARP12UniProtKB:Q9H0J9

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Interferon-induced mono-ART; at the trans-Golgi network it mono-ADP-ribosylates GOLGA1 to support E-cadherin transport.

PMID:25043379

Family-wide assay, the IDA source for PARP12 GO:1990404.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP14 NAD+-protein-glutamate ADP-ribosyltransferase activity

parp14_mart

Participant: Gene Product: PARP14

Gene Product:

PARP14UniProtKB:Q460N5

Function

NAD+-protein-glutamate ADP-ribosyltransferase activityGO:0140807

Substrates: L-glutamyl-[protein]CHEBI:29973 NAD+CHEBI:57540

Products: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 nicotinamideCHEBI:17154

Macrodomain-containing mono-ART that mono-ADP-ribosylates STAT1 on Glu657 and Glu705 and regulates macrophage activation; PARP9 suppresses this activity.

PMID:27796300

PARP14 mono-ADP-ribosylates STAT1.

ADP-ribosylation assays demonstrated that PARP14 has the ability to mono-ADP-ribosylate STAT1

PARP15 NAD+-protein mono-ADP-ribosyltransferase activity

parp15_mart

Participant: Gene Product: PARP15

Gene Product:

PARP15UniProtKB:Q460N3

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Macrodomain-containing PARP14 paralogue; mono-ADP-ribosyltransferase activity in the family-wide assay (IDA).

PMID:25043379

Family-wide assay, the IDA source for PARP15 GO:1990404.

Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity.

PARP16 NAD+-protein-glutamate ADP-ribosyltransferase activity

parp16_mart

Participant: Gene Product: PARP16

Gene Product:

PARP16UniProtKB:Q8N5Y8

Function

NAD+-protein-glutamate ADP-ribosyltransferase activityGO:0140807

Substrates: L-glutamyl-[protein]CHEBI:29973 NAD+CHEBI:57540

Products: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 nicotinamideCHEBI:17154

Locations

endoplasmic reticulum membraneGO:0005789

Tail-anchored ER-membrane mono-ART that modifies ribosomal proteins on glutamate/aspartate, limiting translation; it draws on cytosolic NAD+ made by NMNAT2.

PMID:34314702

PARP16 is a mono-ART that MARylates ribosomal proteins, supported by NMNAT2-made NAD+.

NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins

TIPARP NAD+-protein mono-ADP-ribosyltransferase activity

tiparp_mart

Participant: Gene Product: TIPARP

Gene Product:

TIPARPUniProtKB:Q7Z3E1

Function

NAD+-protein mono-ADP-ribosyltransferase activityGO:1990404

Substrates: NAD+CHEBI:57540

Products: nicotinamideCHEBI:17154

Locations

nucleusGO:0005634

PARP7; aryl hydrocarbon receptor target gene whose mono-ART activity represses AHR transactivation in a negative feedback loop.

PMID:23275542

TIPARP is a mono-ADP-ribosyltransferase.

is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation

NAD+ glycohydrolase / ADP-ribosyl cyclase (CD38, BST1)Molecular Functionnad_glycohydrolase_cyclase

The ectoenzymes CD38 and BST1 (CD157) cleave NAD+ to nicotinamide and either cyclise the ADP-ribose to cyclic ADP-ribose (cADPR) or, far more often, hydrolyse it to ADP-ribose; they also hydrolyse cADPR to ADP-ribose. CD38 hydrolyses roughly 100 NAD+ for each cADPR made and is a dominant NAD+ consumer in many mammalian tissues. cADPR acts as a calcium-mobilising messenger at ryanodine receptors.

Variant set: ADP-ribosyl cyclase paralogue by paralogue (One Or More)

CD38Reactioncd38_variant

Annotons

CD38 NAD+ nucleosidase activity, cyclic ADP-ribose generating

cd38_cyclase

Participant: Gene Product: CD38

Gene Product:

CD38UniProtKB:P28907

Function

NAD+ nucleosidase activity, cyclic ADP-ribose generatingGO:0061809

Substrates: NAD+CHEBI:57540 waterCHEBI:15377

Products: cyclic ADP-riboseCHEBI:73672 ADP-D-riboseCHEBI:57967 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

NAD+ catabolic processGO:0019677

Locations

external side of plasma membraneGO:0009897

Type II transmembrane glycoprotein of leukocytes and many other cells whose C-terminal catalytic domain usually faces outward, though catalytically active intracellular forms exist. It makes cADPR and ADP-ribose and hydrolyses cADPR; under acidic conditions it can also make NAADP (not modelled).

PMID:8253715

Membranes expressing human CD38 convert NAD+ to cADPR and ADP-ribose.

the formation of cADPR was observed in addition to the ADP-ribose (ADPR) formation

PMID:8253715

CD38 hydrolyses cADPR to ADP-ribose.

When the plasma membrane fraction was incubated with cADPR, cADPR was converted to ADPR stoichiometrically

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

RGD records the high NAD+ consumption by CD38.

Of note is the high NAD consumption by Cd38, with hydrolysis of ~100 NAD molecule to yield one cADPR molecule.

BST1 (CD157)Reactionbst1_variant

Annotons

BST1 NAD+ nucleosidase activity, cyclic ADP-ribose generating

bst1_cyclase

Participant: Gene Product: BST1

Gene Product:

BST1UniProtKB:Q10588

Function

NAD+ nucleosidase activity, cyclic ADP-ribose generatingGO:0061809

Substrates: NAD+CHEBI:57540 waterCHEBI:15377

Products: cyclic ADP-riboseCHEBI:73672 ADP-D-riboseCHEBI:57967 nicotinamideCHEBI:17154 H+CHEBI:15378

Processes

NAD+ catabolic processGO:0019677

Locations

external side of plasma membraneGO:0009897

GPI-anchored CD38 paralogue of bone marrow stromal and myeloid cells, with ADP-ribosyl cyclase and cADPR hydrolase activity; its catalytic efficiency is much lower than that of CD38.

PMID:7805847

Soluble human BST1 has ADP-ribosyl cyclase and cADPR hydrolase activity.

purified soluble BST-1 displays both ADP ribosyl cyclase and cADPR hydrolase activities

Part 2: reversal of protein ADP-ribosylation

Hydrolytic removal of protein-linked ADP-riboseMolecular Functionadp_ribose_removal

ADP-ribosylation is reversible. PAR glycohydrolase (PARG) hydrolyses the ribose-ribose bonds of poly(ADP-ribose), releasing free ADP-ribose, but cannot remove the proximal ADP-ribose attached to the protein. The macrodomain hydrolases MACROD1, MACROD2 and OARD1 (TARG1) remove mono-ADP-ribose from glutamate and aspartate residues, again releasing ADP-ribose. ADP-ribose made here and by CD38/BST1 is cleaved further by NUDIX hydrolases, outside this module.

file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0002581.yaml

RGD names PARG, MACROD1, MACROD2 and OARD1 as the erasers of the pathway.

Erasers, such PAR glycohydrolase, the Macro1, Macro2 and Oard1 (TARG1) glycohydrolases, all have a macrodomain fold to bind the modified protein and catalyze ADP-ribosyl hydrolysis.

Variant set: ADP-ribose eraser by linkage hydrolysed (PAR glycosidic bond versus protein-proximal ester bond) (One Or More)

PARG: poly(ADP-ribose) chain hydrolysisReactionparg_variant

Annotons

PARG poly(ADP-ribose) glycohydrolase activity

parg_glycohydrolase

Participant: Gene Product: PARG

Gene Product:

PARGUniProtKB:Q86W56

Function

poly(ADP-ribose) glycohydrolase activityGO:0004649

Substrates: poly(ADP-ribose)CHEBI:142512 waterCHEBI:15377

Products: ADP-D-riboseCHEBI:57967

Processes

protein de-ADP-ribosylationGO:0051725

Locations

nucleusGO:0005634

The only enzyme that hydrolyses PAR chains efficiently, by exo- and endoglycosidic cleavage; it turns over PAR made by PARP1 and PARP2 within minutes of DNA damage.

PMID:23481255

PARG hydrolyses PAR chains but not the protein-proximal ADP-ribose.

PARG is unable to cleave the mono(ADP-ribose) unit directly linked to the protein

Macrodomain mono-ADP-ribosyl hydrolases (MACROD1, MACROD2, OARD1)Molecular Functionmacrodomain_mono_hydrolase_variant

Annotons

MACROD1 ADP-ribosylglutamate-[protein] hydrolase activity

macrod1_hydrolase

Participant: Gene Product: MACROD1

Gene Product:

MACROD1UniProtKB:Q9BQ69

Function

ADP-ribosylglutamate-[protein] hydrolase activityGO:0140293

Substrates: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 waterCHEBI:15377

Products: L-glutamyl-[protein]CHEBI:29973 ADP-D-riboseCHEBI:57967 H+CHEBI:15378

Processes

peptidyl-glutamate ADP-deribosylationGO:0140291

Locations

mitochondrial matrixGO:0005759

Mitochondrially enriched macrodomain hydrolase that removes mono-ADP-ribose from acidic residues; it also deacetylates O-acetyl-ADP-ribose (GO:0019213, IDA).

PMID:23474714

MACROD1, MACROD2 and C6orf130 (OARD1) reverse ARTD10 mono-ADP-ribosylation.

ARTD10-modified targets are substrates for the macrodomain proteins MacroD1, MacroD2 and C6orf130 from Homo sapiens

MACROD2 ADP-ribosylglutamate-[protein] hydrolase activity

macrod2_hydrolase

Participant: Gene Product: MACROD2

Gene Product:

MACROD2UniProtKB:A1Z1Q3

Function

ADP-ribosylglutamate-[protein] hydrolase activityGO:0140293

Substrates: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 waterCHEBI:15377

Products: L-glutamyl-[protein]CHEBI:29973 ADP-D-riboseCHEBI:57967 H+CHEBI:15378

Processes

peptidyl-glutamate ADP-deribosylationGO:0140291

MACROD1 paralogue; reverses PARP10 mono-ADP-ribosylation of GSK3B, restoring kinase activity.

PMID:23474714

MACROD2 reverses PARP10-mediated inhibition of GSK3B.

MacroD2 reversed the ARTD10-catalyzed, mono-ADP-ribose-mediated inhibition of glycogen synthase kinase 3β (GSK3β) in vitro and in cells

OARD1 (TARG1) ADP-ribosylglutamate-[protein] hydrolase activity

oard1_hydrolase

Participant: Gene Product: OARD1

Gene Product:

OARD1UniProtKB:Q9Y530

Function

ADP-ribosylglutamate-[protein] hydrolase activityGO:0140293

Substrates: 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein]CHEBI:142540 waterCHEBI:15377

Products: L-glutamyl-[protein]CHEBI:29973 ADP-D-riboseCHEBI:57967 H+CHEBI:15378

Processes

peptidyl-glutamate ADP-deribosylationGO:0140291

Terminal ADP-ribose protein glycohydrolase that removes the protein-proximal ADP-ribose left by PARG on glutamate residues; its loss causes neurodegeneration in humans. It also deacetylates O-acetyl-ADP-ribose (GO:0061463, IDA).

PMID:23481255

C6orf130/TARG1 (OARD1) removes mono-ADP-ribose from glutamate residues.

identify C6orf130 as a PARP-interacting protein that removes mono(ADP-ribosyl)ation on glutamate amino acid residues in PARP-modified proteins

Part 3: recycling of released nicotinamide to NAD+ (optional)

NAMPT salvage of released nicotinamide back to NAD+nicotinamide_salvage_to_nad

Included by reference to the NAMPT/NMN realization of the NAD+ biosynthesis and salvage module: nicotinamide released by every consumer above is phosphoribosylated by NAMPT to NMN and adenylylated by NMNAT to NAD+, closing the cycle.

Realized by module nad_biosynthesis_salvage#nmn_to_nad_realization