NMNAT1

UniProt ID: Q9HAN9
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

NMNAT1 is the nuclear isoform of nicotinamide/nicotinic acid mononucleotide adenylyltransferase, one of three human NMNAT isoenzymes (NMNAT1 nuclear, NMNAT2 Golgi, NMNAT3 mitochondrial). It catalyses the central, committed adenylyl-transfer step shared by all routes of NAD+ biosynthesis: transfer of an adenylyl group from ATP to nicotinamide mononucleotide (NMN) to form NAD+ with release of pyrophosphate (EC 2.7.7.1), and, with comparable efficiency, to the deamidated substrate nicotinate mononucleotide (NaMN) to form nicotinate adenine dinucleotide (deamido-NAD+/NaAD; EC 2.7.7.18). NMNAT1 therefore sits at the convergence of the de novo (kynurenine), salvage and Preiss-Handler pathways. The enzyme requires a divalent metal cofactor (Zn2+ gives higher activity than Mg2+), assembles into a homohexamer, and is imported into the nucleus via a nuclear localization signal. In the nucleus it supplies NAD+ locally to NAD+-consuming enzymes such as PARP1 and the sirtuin SIRT1, and participates in nuclear ATP generation from poly-ADP-ribose that supports chromatin remodeling. In humans, loss-of-function variants cause Leber congenital amaurosis 9 and the multisystem SHILCA syndrome.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004515 nicotinate-nucleotide adenylyltransferase activity
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic (IBA) call of the NaMN adenylyltransferase (EC 2.7.7.18) activity. This is a core, experimentally verified catalytic function of NMNAT1 and is consistent with UniProt EC 2.7.7.18 and the Reactome NaMN->NaAD reaction.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Reaction=nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity
IBA
GO_REF:0000033
ACCEPT
Summary: Phylogenetic (IBA) call of the NMN adenylyltransferase (EC 2.7.7.1) activity, the defining core molecular function of NMNAT1. Consistent with direct experimental evidence.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0034355 NAD+ biosynthetic process via the salvage pathway
IBA
GO_REF:0000033
KEEP AS NON CORE
Summary: NMNAT1 catalyses the final adenylyl-transfer step of the NAD+ salvage route (NMN -> NAD+). The salvage-pathway framing is correct but narrower than NMNAT1's actual role, since the same enzyme also acts in the de novo and Preiss-Handler routes (NaMN -> NaAD). Retained as a valid, if pathway-specific, biological process annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0005634 nucleus
IBA
GO_REF:0000033
ACCEPT
Summary: NMNAT1 is the nuclear NMNAT isoform, imported via an NLS and confirmed nuclear by immunofluorescence and biochemistry. Core localization.
Supporting Evidence:
PMID:16118205
localization confirmed NMNAT1 to be a nuclear protein, whereas NMNAT2 and -3
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity
IEA
GO_REF:0000120
ACCEPT
Summary: Electronic assertion of the core NMN adenylyltransferase (EC 2.7.7.1) activity, redundant with and confirmed by the direct experimental annotations.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0003824 catalytic activity
IEA
GO_REF:0000002
MARK AS OVER ANNOTATED
Summary: Root-level catalytic activity term from InterPro. Correct but entirely subsumed by the specific adenylyltransferase activities (GO:0000309, GO:0004515); uninformative as a standalone annotation.
GO:0004515 nicotinate-nucleotide adenylyltransferase activity
IEA
GO_REF:0000120
ACCEPT
Summary: Electronic assertion of the core NaMN adenylyltransferase (EC 2.7.7.18) activity, redundant with and confirmed by the direct experimental annotations.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Reaction=nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)
GO:0005634 nucleus
IEA
GO_REF:0000120
ACCEPT
Summary: Electronic nucleus annotation, consistent with the well-established nuclear localization of NMNAT1.
Supporting Evidence:
PMID:16118205
localization confirmed NMNAT1 to be a nuclear protein, whereas NMNAT2 and -3
GO:0006163 purine nucleotide metabolic process
IEA
GO_REF:0000117
MARK AS OVER ANNOTATED
Summary: ARBA electronic annotation. NMNAT1 consumes ATP as an adenylyl donor, but its biological role is NAD+ (pyridine nucleotide) biosynthesis, not purine nucleotide metabolism. This term is over-broad and tangential; the pyridine nucleotide / NAD biosynthesis terms capture the true process.
GO:0009165 nucleotide biosynthetic process
IEA
GO_REF:0000117
KEEP AS NON CORE
Summary: Generic parent of NAD+ biosynthetic process. True but non-specific; retained as a non-core annotation, with GO:0009435 the informative child.
GO:0009435 NAD+ biosynthetic process
IEA
GO_REF:0000120
ACCEPT
Summary: Core biological process. NMNAT1 catalyses the committed adenylyl-transfer step of NAD+ biosynthesis shared by de novo, salvage and Preiss-Handler routes.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0016779 nucleotidyltransferase activity
IEA
GO_REF:0000002
MARK AS OVER ANNOTATED
Summary: InterPro-derived parent term. Correct (NMNAT1 is an adenylyltransferase, a nucleotidyltransferase) but subsumed by the specific EC 2.7.7.1/2.7.7.18 MF terms.
GO:0005515 protein binding
IPI
PMID:19478080
Enzymes in the NAD+ salvage pathway regulate SIRT1 activity ...
KEEP AS NON CORE
Summary: Bare protein binding. This IPI records the functionally meaningful NMNAT1-SIRT1 interaction, in which NMNAT1 is recruited to SIRT1 target promoters to supply nuclear NAD+ for deacetylation. The interaction is informative, but the GO term "protein binding" is uninformative and does not capture the adaptor/NAD+-supply function.
Supporting Evidence:
PMID:19478080
NMNAT-1 interacts with, and is recruited to
GO:0005515 protein binding
IPI
PMID:24722188
Protein interaction network of alternatively spliced isoform...
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a high-throughput brain spliceform interactome screen. Uninformative bare term; retained per policy but marked as over-annotated.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network.
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a proteome-scale interactome map. Uninformative bare term.
GO:0005515 protein binding
IPI
PMID:26871637
Widespread Expansion of Protein Interaction Capabilities by ...
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a high-throughput alternative-splicing interactome screen. Uninformative bare term.
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun...
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a proteome-scale interactome (BioPlex). Uninformative bare term.
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari...
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a high-throughput interactome/variant screen. Uninformative bare term.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome.
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoints from the HuRI reference binary interactome (the largest single source of NMNAT1 protein-binding IPI annotations). Uninformative bare term.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling...
MARK AS OVER ANNOTATED
Summary: Generic protein-binding datapoint from a proteome-scale AP-MS interactome (BioPlex 3.0). Uninformative bare term.
GO:0042802 identical protein binding
IPI
PMID:21516116
Next-generation sequencing to generate interactome datasets.
KEEP AS NON CORE
Summary: Self-interaction. NMNAT1 is a homohexamer in solution, so identical protein binding is biologically real. Kept as a non-core structural annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Homohexamer (PubMed:11751893).
GO:0042802 identical protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network.
KEEP AS NON CORE
Summary: Self-interaction consistent with the NMNAT1 homohexamer. Non-core structural annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Homohexamer (PubMed:11751893).
GO:0042802 identical protein binding
IPI
PMID:25502805
A massively parallel pipeline to clone DNA variants and exam...
KEEP AS NON CORE
Summary: Self-interaction consistent with the NMNAT1 homohexamer. Non-core structural annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Homohexamer (PubMed:11751893).
GO:0042802 identical protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari...
KEEP AS NON CORE
Summary: Self-interaction consistent with the NMNAT1 homohexamer. Non-core structural annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Homohexamer (PubMed:11751893).
GO:0042802 identical protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome.
KEEP AS NON CORE
Summary: Self-interaction consistent with the NMNAT1 homohexamer. Non-core structural annotation.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Homohexamer (PubMed:11751893).
GO:0005654 nucleoplasm
IDA
GO_REF:0000052
ACCEPT
Summary: Immunofluorescence (HPA) localization to the nucleoplasm, consistent with the nuclear localization of NMNAT1. Core localization at finer granularity than nucleus.
GO:0016604 nuclear body
IDA
GO_REF:0000052
KEEP AS NON CORE
Summary: HPA immunofluorescence detection in nuclear bodies. Plausible sub-nuclear compartment but not a core, functionally established localization; kept as non-core.
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity
EXP
PMID:17402747
Initial-rate kinetics of human NMN-adenylyltransferases: sub...
ACCEPT
Summary: Direct experimental (initial-rate kinetics) evidence for the core NMN adenylyltransferase (EC 2.7.7.1) activity. Defining molecular function.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0004515 nicotinate-nucleotide adenylyltransferase activity
EXP
PMID:17402747
Initial-rate kinetics of human NMN-adenylyltransferases: sub...
ACCEPT
Summary: Direct experimental (initial-rate kinetics) evidence for the core NaMN adenylyltransferase (EC 2.7.7.18) activity; NMNAT1 uses NaMN with the same efficiency as NMN. Defining molecular function.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Reaction=nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity
IDA
PMID:16118205
Subcellular compartmentation and differential catalytic prop...
ACCEPT
Summary: Direct assay of NMN adenylyltransferase activity for the NMNAT1 isoform. Core molecular function.
Supporting Evidence:
PMID:16118205
as opposed to preferred NAD+ synthesis by
GO:0045892 negative regulation of DNA-templated transcription
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: Sequence-similarity (By similarity, from mouse Nmnat1) transfer. NMNAT1 contributes to transcriptional repression through its role in supplying nuclear NAD+ to SIRT1 and directing PARP1 activity at chromatin. A real but indirect, non-core regulatory role that depends on the catalytic/adaptor functions.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
ADP-ribosylation by directing PARP1 catalytic activity to glutamate and
GO:0140768 protein ADP-ribosyltransferase-substrate adaptor activity
ISS
GO_REF:0000024
KEEP AS NON CORE
Summary: By-similarity (from mouse Nmnat1) activity: NMNAT1 acts as a cofactor that directs PARP1 catalytic activity toward glutamate/aspartate residues on histones, i.e. an ADP-ribosyltransferase-substrate adaptor. A genuine moonlighting function distinct from the core NAD+-synthetic activity; kept as non-core.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
ADP-ribosylation by directing PARP1 catalytic activity to glutamate and
GO:0009165 nucleotide biosynthetic process
IC
PMID:16118205
Subcellular compartmentation and differential catalytic prop...
KEEP AS NON CORE
Summary: Curator inference (from the NaMN adenylyltransferase activity) of the generic parent process. True but non-specific relative to NAD+ biosynthetic process; kept as non-core.
GO:1990966 ATP generation from poly-ADP-D-ribose
IDA
PMID:27257257
ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is requir...
KEEP AS NON CORE
Summary: Direct evidence that NMNAT1 participates (with PARP1, PARG and NUDT5/NUDIX5) in nuclear ATP generation from poly-ADP-ribose that supports chromatin remodeling. A real but specialized, non-core niche role.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
ATP in the nucleus, together with PARP1, PARG and NUDT5
GO:0005634 nucleus
HDA
PMID:21630459
Proteomic characterization of the human sperm nucleus.
ACCEPT
Summary: High-throughput proteomic detection of NMNAT1 in the human sperm nucleus. Consistent with the established nuclear localization.
Supporting Evidence:
PMID:16118205
localization confirmed NMNAT1 to be a nuclear protein, whereas NMNAT2 and -3
GO:0004515 nicotinate-nucleotide adenylyltransferase activity
IDA
PMID:16118205
Subcellular compartmentation and differential catalytic prop...
ACCEPT
Summary: Direct assay of NaMN adenylyltransferase (EC 2.7.7.18) activity for the NMNAT1 isoform. Core molecular function.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Reaction=nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)
GO:0005634 nucleus
IDA
PMID:16118205
Subcellular compartmentation and differential catalytic prop...
ACCEPT
Summary: Direct immunofluorescence localization of the NMNAT1 isoform to the nucleus. Core localization.
Supporting Evidence:
PMID:16118205
localization confirmed NMNAT1 to be a nuclear protein, whereas NMNAT2 and -3
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-200512
ACCEPT
Summary: Reactome-curated nucleoplasm location for the NMNAT1 NaMN->NaAD reaction. Consistent with nuclear localization.
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity
IDA
PMID:11027696
Molecular cloning, chromosomal localization, tissue mRNA lev...
ACCEPT
Summary: Direct assay of NMN adenylyltransferase (EC 2.7.7.1) activity for the recombinant human enzyme (primary characterization). Core molecular function.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Catalyzes the formation of NAD(+) from nicotinamide
GO:0005515 protein binding
IPI
PMID:11248244
Characterization of recombinant human nicotinamide mononucle...
KEEP AS NON CORE
Summary: Bare protein binding, but this IPI captures the functionally meaningful physical interaction with PARP1 (UniProtKB:P09874) demonstrated in the primary NMNAT1 characterization, where NMNAT1 strongly inhibits PARP1. The interaction is informative; the GO term itself is uninformative, so kept as non-core.
Supporting Evidence:
file:human/NMNAT1/NMNAT1-uniprot.txt
Interacts with ADPRT/PARP1
GO:0005634 nucleus
IDA
PMID:11248244
Characterization of recombinant human nicotinamide mononucle...
ACCEPT
Summary: Direct evidence (immunofluorescence confirming the predicted NLS) for nuclear localization from the primary characterization. Core localization.
Supporting Evidence:
PMID:11248244
putative nuclear localization signal was confirmed by immunofluorescence

Core Functions

Nicotinamide mononucleotide (NMN) adenylyltransferase: transfers an adenylyl group from ATP to NMN to form NAD+ with release of pyrophosphate (EC 2.7.7.1), the committed step of NAD+ biosynthesis via NMN.

Supporting Evidence:
  • file:human/NMNAT1/NMNAT1-uniprot.txt
    Catalyzes the formation of NAD(+) from nicotinamide
  • PMID:16118205
    as opposed to preferred NAD+ synthesis by

Nicotinate mononucleotide (NaMN) adenylyltransferase: transfers an adenylyl group from ATP to NaMN to form nicotinate adenine dinucleotide (deamido-NAD+/NaAD) with release of pyrophosphate (EC 2.7.7.18); NMNAT1 uses the deamidated NaMN with comparable efficiency, linking the Preiss-Handler and de novo routes.

Supporting Evidence:
  • file:human/NMNAT1/NMNAT1-uniprot.txt
    Reaction=nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)

References

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Notes

(NMNAT1-notes.md)

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