NMNAT3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004515 nicotinate-nucleotide adenylyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: NaMN + ATP produces deamido-NAD+ (NaAD); adenylyltransferase activity (EC 2.7.7.18). This is a core catalytic function of NMNAT3, directly demonstrated for the human enzyme by IDA/EXP (PMID:16118205, PMID:17402747). The phylogenetic (IBA) inference is fully consistent with the experimental annotations. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+)
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: NMN + ATP produces NAD+; adenylyltransferase activity (EC 2.7.7.1). This is the central catalytic function of NMNAT3, directly demonstrated for the human enzyme (PMID:16118205, PMID:17402747). The IBA inference agrees with the experimental evidence and is accepted. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt beta-nicotinamide D-ribonucleotide + ATP + H(+) = diphosphate
GO:0034355 NAD+ biosynthetic process via the salvage pathway	IBA GO_REF:0000033	ACCEPT	Summary: NMNAT catalyzes the final, shared step of the NAD+ salvage pathway (NMN, regenerated from nicotinamide via NAMPT, is adenylylated to NAD+). This is an appropriate, more specific BP than the bare NAD+ biosynthetic process term and is consistent with NMNAT3 demonstrated enzymology. Kept. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt Cofactor biosynthesis; NAD(+) biosynthesis; NAD(+) from
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: NMNAT3 is the mitochondrial NMNAT isoform; the phylogenetic is_active_in mitochondrion annotation matches the experimentally determined localization (PMID:16118205, PMID:12574164) and UniProt SUBCELLULAR LOCATION. Core location. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (multi-method, RHEA/EC-mapped) assignment of the core NMN adenylyltransferase activity (EC 2.7.7.1). Redundant with, and confirmed by, the experimental IDA/EXP annotations of the same term. Accepted.
GO:0003824 catalytic activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based assignment of the root catalytic activity term. Correct but uninformative given the specific EC 2.7.7.1 / 2.7.7.18 adenylyltransferase activities are annotated. Over-general parent, not a core function statement.
GO:0004515 nicotinate-nucleotide adenylyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA/EC-mapped) assignment of the NaMN adenylyltransferase activity (EC 2.7.7.18), redundant with and confirmed by the experimental IDA/EXP annotations of the same term. Accepted.
GO:0005739 mitochondrion	IEA GO_REF:0000044	ACCEPT	Summary: UniProt SubCell-vocabulary electronic transfer of the mitochondrial localization, consistent with experimental data (PMID:16118205, PMID:12574164). Accepted. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion
GO:0005759 mitochondrial matrix	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic assignment to the mitochondrial matrix, the specific sub-compartment expected for a soluble mitochondrial NAD+-biosynthetic enzyme and concordant with the Reactome TAS annotation. Reasonable; kept.
GO:0009165 nucleotide biosynthetic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Correct but over-general parent of NAD+ biosynthetic process. The specific terms GO:0009435 / GO:0034355 are annotated and preferred. Over-annotation of a broad parent.
GO:0009435 NAD+ biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Core biological process for NMNAT3; NAD+ biosynthesis is the pathway of which the NMNAT step is the terminal reaction (UniProt PATHWAY). Well supported. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt Cofactor biosynthesis; NAD(+) biosynthesis
GO:0016779 nucleotidyltransferase activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based assignment of the broad nucleotidyltransferase parent. Correct but over-general; the specific adenylyltransferase activities (EC 2.7.7.1 / 2.7.7.18) are the informative MF terms. Over-annotation of a parent.
GO:0030424 axon	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer from a rat ortholog (Ensembl Compara, ENSRNOP00000018411). Axonal localization is characteristic of NMNAT2 (Golgi/axonally transported), not of the mitochondrial NMNAT3. Not supported for human NMNAT3 by any primary data here; appears to be mis-transfer/over-annotation. Cannot fully refute the orthology transfer, but it is not a core NMNAT3 location.
GO:0034612 response to tumor necrosis factor	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer from a rat ortholog (Ensembl Compara). No primary evidence links human NMNAT3 to a TNF response; this is peripheral at best and looks like an over-propagated orthology-based inference. Not a core function.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer from a rat ortholog (Ensembl Compara). Neuronal-compartment localization is not supported for the mitochondrial human NMNAT3 by primary data and reflects the neuroprotective biology of NMNAT2/NMNAT1 rather than NMNAT3. Over-annotation.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence (IDA) localizing NMNAT3 to the mitochondrion, corroborating the experimentally established mitochondrial localization. Core location; accepted.
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity	IDA PMID:16118205 Subcellular compartmentation and differential catalytic prop...	ACCEPT	Summary: Direct assay of the human NMNAT3 isoform demonstrating NMN adenylyltransferase (NAD+-synthesizing) activity, with characterization of its distinctive broad substrate tolerance. This is a primary experimental basis for the core MF. Accepted. Supporting Evidence: PMID:16118205 particularly NMNAT3 exhibits a high tolerance toward substrate modifications
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity	EXP PMID:17402747 Initial-rate kinetics of human NMN-adenylyltransferases: sub...	ACCEPT	Summary: Initial-rate kinetic characterization of human NMNAT3 confirming NMN adenylyltransferase activity (EC 2.7.7.1), including its distinctive substrate binding order and efficient use of ITP. Primary experimental support for the core MF. Accepted. Supporting Evidence: PMID:17402747 the opposite order is observed with the mitochondrial isozyme NMNAT3. Only the latter utilizes ITP efficiently in place of ATP
GO:0004515 nicotinate-nucleotide adenylyltransferase activity	EXP PMID:17402747 Initial-rate kinetics of human NMN-adenylyltransferases: sub...	ACCEPT	Summary: Kinetic characterization confirming human NMNAT3 also adenylylates the deamidated substrate NaMN (EC 2.7.7.18), a core catalytic activity. Accepted. Supporting Evidence: PMID:17402747 substrate specificities, and metal ion preferences for the three isozymes of human nicotinamide mononucleotide adenylyl-transferase
GO:0005739 mitochondrion	EXP PMID:12574164 Structural characterization of a human cytosolic NMN/NaMN ad...	ACCEPT	Summary: Experimental characterization of human NMNAT3 (hsPNAT-3) reporting cytoplasmic and mitochondrial localization. Supports the mitochondrion annotation (a cytosolic pool is also reported; Reactome annotates the mitochondrial form). Core location; accepted. Supporting Evidence: PMID:12574164 human PNAT (hsPNAT-3) that is located in the cytoplasm and mitochondria
GO:0000309 nicotinamide-nucleotide adenylyltransferase activity	IDA PMID:26616331 Alternative splicing of Drosophila Nmnat functions as a swit...	ACCEPT	Summary: NMN adenylyltransferase activity is a firmly established core function of human NMNAT3. This particular citation (Ruan et al. 2015) is primarily a study of Drosophila Nmnat splice variants and mentions human NMNAT3 splice variants only in passing, so it is a weaker source for this human annotation than PMID:16118205 / PMID:17402747; but the annotated activity is correct and I defer to the curator on the experimental basis. Accepted (not core-defining beyond what the two primary human enzymology papers already establish). Supporting Evidence: PMID:26616331 two splice variants of human NMNAT3 (v1 and V3-FKSG76) have
GO:0006457 protein folding	IDA PMID:18344983 NAD synthase NMNAT acts as a chaperone to protect against ne...	KEEP AS NON CORE	Summary: The chaperone/protein-folding function of NMNAT was demonstrated for Drosophila NMNAT (DmNMNAT) in Zhai et al. 2008; it was not directly assayed on the human mitochondrial NMNAT3 isoform. This is a real, family-level NMNAT activity but is peripheral to NMNAT3 core mitochondrial NAD+-synthesis role and not directly established for the human protein. Retained as non-core (experimental IDA; not removed). Supporting Evidence: PMID:18344983 NMNAT displays chaperone function both in biochemical assays and
GO:0044183 protein folding chaperone	IDA PMID:18344983 NAD synthase NMNAT acts as a chaperone to protect against ne...	KEEP AS NON CORE	Summary: Chaperone (protein-folding) molecular function attributed via the Drosophila NMNAT chaperone study (Zhai et al. 2008), which additionally notes structural similarity to known chaperones. Not directly demonstrated for human mitochondrial NMNAT3; a family-level function peripheral to its core catalytic role. Retained as non-core (experimental IDA; not removed). Supporting Evidence: PMID:18344983 it shares significant structural similarity with known
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: High-throughput mitochondrial-proteome identification placing NMNAT3 in the mitochondrion, consistent with the experimentally established localization. Accepted as supporting the core location.
GO:0009165 nucleotide biosynthetic process	IC PMID:16118205 Subcellular compartmentation and differential catalytic prop...	MARK AS OVER ANNOTATED	Summary: Curator inference (from the demonstrated adenylyltransferase activity, GO:0004515) of the broad nucleotide biosynthetic process term. Correct but over-general relative to the specific NAD+ biosynthetic process (GO:0009435 / GO:0034355) that is also annotated. Over-annotation of a broad parent.
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-200474	ACCEPT	Summary: Reactome (TAS) places the NMNAT3-catalyzed NaMN to NaAD reaction in the mitochondrial matrix, the expected sub-compartment for this soluble enzyme. A more specific, well-supported location than mitochondrion; accepted.
GO:0004515 nicotinate-nucleotide adenylyltransferase activity	IDA PMID:16118205 Subcellular compartmentation and differential catalytic prop...	ACCEPT	Summary: Direct assay of human NMNAT3 demonstrating adenylyltransferase activity on the deamidated substrate NaMN (EC 2.7.7.18), catalyzed with efficiency comparable to the amidated (NMN) substrate. Primary experimental support for the core MF. Accepted. Supporting Evidence: file:human/NMNAT3/NMNAT3-uniprot.txt nicotinic acid mononucleotide (NaMN) as substrate with the same
GO:0005739 mitochondrion	IDA PMID:16118205 Subcellular compartmentation and differential catalytic prop...	ACCEPT	Summary: Direct (subcellular fractionation/localization) evidence that NMNAT3 is the mitochondrial isoform. This is the primary experimental basis for the core mitochondrial localization. Accepted. Supporting Evidence: PMID:16118205 whereas NMNAT2 and -3 were localized to the Golgi complex and the mitochondria, respectively

Gene Description

Existing Annotations Review

Core Functions

Catalyzes the central NAD+-biosynthetic adenylyl-transfer step, condensing nicotinamide mononucleotide (NMN) with the AMP moiety of ATP to form NAD+ (with release of pyrophosphate), supplying the mitochondrial NAD+ pool.

Catalyzes the equivalent adenylyl-transfer step on the deamidated substrate nicotinate mononucleotide (NaMN), condensing it with ATP to form deamido-NAD+ (NaAD) plus pyrophosphate; NMNAT3 uses NaMN with efficiency comparable to NMN, feeding the Preiss-Handler/de novo branch of NAD+ synthesis.

References

📚 Additional Documentation

Notes

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