NANS

Gene Description

NANS (N-acetylneuraminate-9-phosphate synthase, also called sialic acid synthase or sialic acid phosphate synthase; EC 2.5.1.57) is a cytosolic enzyme that catalyzes the committed condensation step of de novo sialic acid (Neu5Ac) biosynthesis. It condenses phosphoenolpyruvate (PEP) with N-acetylmannosamine 6-phosphate (ManNAc-6-P, produced by GNE) to form N-acetylneuraminate 9-phosphate (Neu5Ac-9-P), which is subsequently dephosphorylated (NANP) and activated to CMP-sialic acid (CMAS) for use by sialyltransferases. NANS can also condense PEP with D-mannose 6-phosphate to produce the 9-phosphate of deaminoneuraminic acid (KDN-9-P, EC 2.5.1.132), though with much lower activity than toward the N-acetyl product. The protein is homologous to the bacterial sialic acid synthase NeuB and comprises an N-terminal (beta/alpha)8 TIM-barrel catalytic domain and a C-terminal antifreeze-like (AFP-like/SAF) domain. Biallelic loss-of-function variants cause NANS deficiency (spondyloepimetaphyseal dysplasia, Genevieve type; SEMDG), an autosomal recessive disorder of infantile-onset developmental delay, intellectual disability, skeletal dysplasia and short stature, with accumulation of N-acetylmannosamine.

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0047444 N-acylneuraminate-9-phosphate synthase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function, inferred from the phylogenetic tree (NeuB/sialic acid synthase family). Matches EC 2.5.1.57 and the experimentally characterized reaction (PEP + ManNAc-6-P -> Neu5Ac-9-P). Accept as a representative core function. Supporting Evidence: PMID:10749855 In vitro the human enzyme uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of Neu5Ac and KDN, respectively, but exhibits much higher activity toward the Neu5Ac phosphate product.
GO:0006054 N-acetylneuraminate metabolic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Correct but general parent process; GO:0046380 (N-acetylneuraminate biosynthetic process) is the more specific and accurate core BP for NANS. Keep as non-core.
GO:0016051 carbohydrate biosynthetic process	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: High-level InterPro-derived process term. Correct (sialic acids are amino sugars) but very general relative to the specific sialic acid biosynthetic process. Keep as non-core.
GO:0047444 N-acylneuraminate-9-phosphate synthase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation mapped from EC 2.5.1.57 / RHEA:80835, matching the curated catalytic activity of NANS. Correct core molecular function.
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	Summary: NANS is a soluble cytosolic enzyme of de novo sialic acid biosynthesis; cytosol is the correct site of activity, consistent with the Reactome TAS annotation. Accept.
GO:0047444 N-acylneuraminate-9-phosphate synthase activity	TAS Reactome:R-HSA-4084976	ACCEPT	Summary: Reactome traceable annotation for the NANS reaction (ManNAc-6-P -> Neu5Ac-9-P). Correct core molecular function. Supporting Evidence: Reactome:R-HSA-4084976 Sialic acid synthase (NANS, SAS) can convert N-acetylmannosamine 6-phosphate (ManNAc-6-P) to N-acetylneuraminate 9-phosphate (Neu5Ac-9-P) (Lawrence et al. 2000).
GO:0005654 nucleoplasm	IDA GO_REF:0000052	MARK AS OVER ANNOTATED	Summary: From HPA immunofluorescence (GO_REF:0000052). NANS is a cytosolic sialic-acid-synthesis enzyme with no described nuclear role or nuclear-targeting features; nucleoplasm localization is not supported by its biology and is very likely an over-call of the immunofluorescence signal. Retained (IDA, not removed) but flagged as over-annotated.
GO:0006055 CMP-N-acetylneuraminate biosynthetic process	IMP PMID:31121216 Activity of N-acylneuraminate-9-phosphatase (NANP) is not es...	KEEP AS NON CORE	Summary: NANS knockout abolishes CMP-sialic acid in human cells, so NANS is functionally required for CMP-Neu5Ac production. However, CMP-Neu5Ac is the downstream pathway product (made by CMAS after NANP dephosphorylation); NANS's own step yields Neu5Ac-9-P. Correct pathway-level involvement but not the core BP for NANS; keep as non-core. Supporting Evidence: PMID:31121216 CMP-sialic acid was dramatically reduced in GNE and NANS KO cells and undetectable in CMAS KO.
GO:0046380 N-acetylneuraminate biosynthetic process	IMP PMID:31121216 Activity of N-acylneuraminate-9-phosphatase (NANP) is not es...	ACCEPT	Summary: Core biological process. NANS catalyzes the committed step of de novo Neu5Ac biosynthesis; its knockout reduces cellular sialylation and sialic acid, directly supporting involvement in N-acetylneuraminate biosynthetic process. Accept. Supporting Evidence: PMID:31121216 Sialylation of cell surface glycans was reduced by KO of GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), NANS (sialic acid synthase) and CMAS (N-acylneuraminate cytidylyltransferase) genes
GO:0047444 N-acylneuraminate-9-phosphate synthase activity	IDA PMID:10749855 Cloning and expression of the human N-acetylneuraminic acid ...	ACCEPT	Summary: Direct experimental characterization of the human enzyme, which uses ManNAc-6-P (and, less efficiently, Man-6-P) with PEP to form the 9-phosphate products. This is the primary evidence for the core molecular function. Accept. Supporting Evidence: PMID:10749855 In vitro the human enzyme uses N-acetylmannosamine 6-phosphate and mannose 6-phosphate as substrates to generate phosphorylated forms of Neu5Ac and KDN, respectively, but exhibits much higher activity toward the Neu5Ac phosphate product.
GO:0006055 CMP-N-acetylneuraminate biosynthetic process	NAS PMID:10749855 Cloning and expression of the human N-acetylneuraminic acid ...	KEEP AS NON CORE	Summary: Author-stated pathway-level involvement; NANS acts upstream of CMP-Neu5Ac formation. As above, this is the downstream pathway product rather than NANS's direct catalytic output (Neu5Ac-9-P). Keep as non-core.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Based on high-throughput mass-spec detection of NANS in urinary prostatic-secretion exosome preparations. Abundant cytosolic enzymes are frequently reported in such exosome/HTP proteomes; this does not represent a functional localization for a cytosolic sialic acid biosynthesis enzyme. Retained (HDA, not removed) but flagged as over-annotated. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected.
GO:0005829 cytosol	TAS Reactome:R-HSA-4084976	ACCEPT	Summary: Correct cytosolic localization for this soluble sialic-acid-synthesis enzyme (Reactome traceable annotation). Accept.
GO:0005737 cytoplasm	NAS PMID:10749855 Cloning and expression of the human N-acetylneuraminic acid ...	KEEP AS NON CORE	Summary: Author-stated cytoplasmic localization. Correct but less specific than cytosol (GO:0005829), which is the preferred location term for NANS. Keep as non-core.

Gene Description

Existing Annotations Review

Core Functions

Cytosolic condensation of phosphoenolpyruvate with N-acetylmannosamine 6-phosphate to form N-acetylneuraminate 9-phosphate, the committed step of de novo sialic acid (Neu5Ac) biosynthesis; the enzyme can also use mannose 6-phosphate to form KDN 9-phosphate.

References

📚 Additional Documentation

Notes

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