Sialic acid (N-acetylneuraminate) metabolism (biosynthesis, activation, transport, catabolism)

Sialic acids (in humans chiefly N-acetylneuraminate, Neu5Ac) are the negatively charged nine-carbon sugars that cap most cell-surface and secreted glycoconjugates, governing cell-cell recognition, receptor masking, serum-protein half-life and pathogen interactions. Their metabolism forms a compact cytosol-to- organelle pathway. Biosynthesis starts with the bifunctional, feedback-controlled enzyme GNE, whose epimerase domain converts UDP-N-acetylglucosamine to N-acetylmannosamine (ManNAc) and whose kinase domain phosphorylates ManNAc to ManNAc-6-phosphate. The sialic-acid synthase NANS then condenses ManNAc-6-P with phosphoenolpyruvate to N-acetylneuraminate-9-phosphate, which the HAD phosphatase NANP dephosphorylates to free Neu5Ac. In the nucleus, CMAS activates Neu5Ac with CTP to the sugar-nucleotide donor CMP-Neu5Ac; the Golgi antiporter SLC35A1 imports CMP-Neu5Ac into the Golgi lumen (in exchange for CMP) to supply the sialyltransferases that decorate glycans. CMP-Neu5Ac feedback-inhibits GNE, keeping flux matched to demand. On the catabolic side, the lysosomal sialidase NEU1 (acting within the CTSA/GLB1 lysosomal multienzyme complex) removes terminal sialic acids from glycoconjugates during turnover, the lysosomal H+/sialic acid symporter sialin (SLC17A5) exports the released free sialic acid to the cytosol for reuse by CMAS, and the cytosolic aldolase NPL cleaves free Neu5Ac to ManNAc + pyruvate, recycling the amino sugar. Inherited defects at nearly every step cause disease: GNE myopathy and sialuria (GNE), NANS-CDG, SLC35A1-CDG (CDG-IIf), sialidosis (NEU1), free sialic acid storage disorders (Salla disease and infantile sialic acid storage disease; SLC17A5) and an NPL-related myopathy. Several of these respond to ManNAc or sialic-acid supplementation.

MODULE:sialic_acid_metabolismDRAFTMetabolic Pathwaymodules/sialic_acid_metabolism.yaml
N-acetylneuraminate biosynthetic processGO:0046380 N-acetylneuraminate catabolic processGO:0019262
GO:0046380
N-acetylneuraminate biosynthetic process
GNE, NANS, NANP and CMAS carry out sialic acid (Neu5Ac) biosynthesis and activation (GO:0046380).
GO:0019262
N-acetylneuraminate catabolic process
NEU1 and NPL carry out sialic acid catabolism/recycling (GO:0019262).
file:human/GNE/GNE-ai-review.yaml
GNE gene review (human)
The UDP-GlcNAc->ManNAc->ManNAc-6-P step (UniProtKB:Q9Y223, GO:0008761/GO:0009384) matches the completed human GNE review.
file:human/NANS/NANS-ai-review.yaml
NANS gene review (human)
The ManNAc-6-P + PEP -> Neu5Ac-9-P step (UniProtKB:Q9NR45, GO:0047444) matches the completed human NANS review.
file:human/NANP/NANP-ai-review.yaml
NANP gene review (human)
The Neu5Ac-9-P -> Neu5Ac dephosphorylation step (UniProtKB:Q8TBE9, GO:0050124) matches the completed human NANP review.
file:human/CMAS/CMAS-ai-review.yaml
CMAS gene review (human)
The Neu5Ac + CTP -> CMP-Neu5Ac activation step (UniProtKB:Q8NFW8, GO:0008781) matches the completed human CMAS review.
file:human/SLC35A1/SLC35A1-ai-review.yaml
SLC35A1 gene review (human)
The Golgi CMP-Neu5Ac import step (UniProtKB:P78382, GO:0005456) matches the completed human SLC35A1 review.
file:human/NEU1/NEU1-ai-review.yaml
NEU1 gene review (human)
The lysosomal desialylation step (UniProtKB:Q99519, GO:0004308) matches the completed human NEU1 review.
file:human/NPL/NPL-ai-review.yaml
NPL gene review (human)
The Neu5Ac -> ManNAc + pyruvate recycling step (UniProtKB:Q9BXD5, GO:0008747) matches the completed human NPL review.
PMID:41655697
Biosynthetic and genetic pathways related to sialic acid metabolism.
2026 review used to audit the module. It places lysosomal export of free sialic acid by SLC17A5 between lysosomal NEU1 and cytosolic reuse by CMAS or cleavage by NPL, a step missing from the earlier version of this module. It also reports that NANP is dispensable for Neu5Ac production in HAP1 cells, and that NAGK may phosphorylate ManNAc, although that role is not established.
Cytosolic Neu5Ac is mainly derived from the lysosomal salvage pathway (60), where it is cleaved from glycoconjugates by lysosomal NEU1 and transported into the cytoplasm via the lysosomal sialin transporter SLC17A5 (Fig. 1).
PMID:15510212
Functional characterization of wild-type and mutant human sialin.
Primary functional evidence that human sialin (SLC17A5, UniProtKB:Q9NRA2) exports free sialic acid from lysosomes by proton-coupled transport. GOA records EXP annotations to GO:0015538 sialic acid:proton symporter activity from this paper.
Sialic acids cleaved off from degraded sialoglycoconjugates are exported from lysosomes by a membrane transporter, named sialin, which is defective in two allelic inherited diseases: infantile sialic acid storage disease (ISSD) and Salla disease.
PMID:10581036
A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.
Identifies SLC17A5 as the gene mutated in Salla disease and infantile sialic acid storage disease, the lysosomal free sialic acid storage disorders.
Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.
PMID:31121216
Activity of N-acylneuraminate-9-phosphatase (NANP) is not essential for de novo sialic acid biosynthesis.
In knockout cell lines, CMP-sialic acid and cell-surface sialylation persist without NANP even though Neu5Ac-9-P accumulates. An unidentified alternative phosphatase can therefore bypass the NANP step.
Our data provide evidence that NANP activity is not essential for de novo sialic acid production and point towards an alternative phosphatase activity, bypassing NANP.
9Nodes
8Parts
0Variant Sets
0Variants
8Annotons
8Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:sialic_acid_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.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 8 evidence or coverage gap(s) (16 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.

AnnotonParticipantFunctionAssessment
gne_activity GNE (human)
UniProtKB:Q9Y223
Family Representative 		UDP-N-acetylglucosamine 2-epimerase + N-acylmannosamine kinase activity
GO:0008761 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nans_activity NANS (human)
UniProtKB:Q9NR45
Family Representative 		N-acylneuraminate-9-phosphate synthase activity
GO:0047444 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nanp_activity NANP (human)
UniProtKB:Q8TBE9
Family Representative 		N-acylneuraminate-9-phosphatase activity
GO:0050124 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cmas_activity CMAS (human)
UniProtKB:Q8NFW8
Family Representative 		N-acylneuraminate cytidylyltransferase activity
GO:0008781 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc35a1_activity SLC35A1 (human)
UniProtKB:P78382
Family Representative 		CMP-N-acetylneuraminate transmembrane transporter activity
GO:0005456 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
neu1_activity NEU1 (human)
UniProtKB:Q99519
Family Representative 		exo-alpha-sialidase activity
GO:0004308 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
slc17a5_activity SLC17A5 (human)
UniProtKB:Q9NRA2
Family Representative 		sialic acid:proton symporter activity
GO:0015538 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
npl_activity NPL (human)
UniProtKB:Q9BXD5
Family Representative 		N-acetylneuraminate lyase activity
GO:0008747 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gne_activity GNE / bifunctional UDP-GlcNAc 2-epimerase-kinase family
PANTHER:PTHR18964
Family 		UDP-N-acetylglucosamine 2-epimerase + N-acylmannosamine kinase activity
GO:0008761 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR18964.
nans_activity NANS / N-acetylneuraminate-9-phosphate synthase family
PANTHER:PTHR42966
Family 		N-acylneuraminate-9-phosphate synthase activity
GO:0047444 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR42966.
nanp_activity NANP / HAD N-acylneuraminate-9-phosphatase family
PANTHER:PTHR46470
Family 		N-acylneuraminate-9-phosphatase activity
GO:0050124 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR46470.
cmas_activity CMAS / N-acylneuraminate cytidylyltransferase family
PANTHER:PTHR21485
Family 		N-acylneuraminate cytidylyltransferase activity
GO:0008781 		Family Supported
Family review supports GO:0008781 FAMILY_WIDE. The family has two subfamilies and both hold genuine CMP-Neu5Ac synthetases (CMAS in SF3; NeuA, including E. coli K1 NeuA, in SF6), so the term is scoped to the whole family, but both subfamilies are mixed and the members it is false for are listed as exceptions. Every reviewed member was checked: the KdsC-type and KDN-9-P phosphatases lack the transferase, and the PseF/LegF-type enzymes use other nonulosonic acids. All of these are listed as member exceptions.
slc35a1_activity SLC35A1 / nucleotide-sugar transporter family
PANTHER:PTHR10231
Family 		CMP-N-acetylneuraminate transmembrane transporter activity
GO:0005456 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10231.
neu1_activity NEU / sialidase (neuraminidase) family
PANTHER:PTHR10628
Family 		exo-alpha-sialidase activity
GO:0004308 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR10628.
slc17a5_activity SLC17A5 / sialin subfamily of the SLC17 anion transporters
PANTHER:PTHR11662:SF432
Family 		sialic acid:proton symporter activity
GO:0015538 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR11662:SF432.
npl_activity NPL / N-acetylneuraminate lyase family
PANTHER:PTHR12128
Family 		N-acetylneuraminate lyase activity
GO:0008747 		Family Scope Restricted
GO:0008747 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. SF21 is uniformly vertebrate NPL in the Swiss-Prot entries, and the PAINT node is seeded by human, pig and mouse NPL.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • neu5ac_to_cmpneu5ac ⊣ udpglcnac_to_mannac6p [closed]
    neu5ac_to_cmpneu5ac is regulated by neu5ac9p_to_neu5ac, lysosomal_sialic_acid_export: feedback loop closed

Gene-review completeness (7/8 grounded genes reviewed)

7 complete review(s) · 0 with deep research · 1 missing review · 7 reviewed but lacking deep research

Gene Review Complete Deep research
CMAS Q8NFW8 ✓ ✓ ✗
GNE Q9Y223 ✓ ✓ ✗
NANP Q8TBE9 ✓ ✓ ✗
NANS Q9NR45 ✓ ✓ ✗
NEU1 Q99519 ✓ ✓ ✗
NPL Q9BXD5 ✓ ✓ ✗
SLC17A5 (human) Q9NRA2 ✗ — —
SLC35A1 P78382 ✓ ✓ ✗

Details

Context
cytosolGO:0005829 nucleusGO:0005634 Golgi membraneGO:0000139 lysosomal lumenGO:0043202 lysosomal membraneGO:0005765
Sialic acid (N-acetylneuraminate) metabolismMetabolic Pathwaysialic_acid_metabolism
N-acetylneuraminate biosynthetic processGO:0046380 N-acetylneuraminate catabolic processGO:0019262
Context
cytosolGO:0005829 nucleusGO:0005634 Golgi membraneGO:0000139 lysosomal lumenGO:0043202 lysosomal membraneGO:0005765

Sialic acid (Neu5Ac) metabolism (GO:0046380 biosynthesis + GO:0019262 catabolism), grounded to seven completed human gene reviews, each a distinct PANTHER family, plus the lysosomal sialic acid exporter SLC17A5 (added after the 2026 review PMID:41655697; no gene review yet, grounded to UniProtKB:Q9NRA2, GOA EXP annotations to GO:0015538 and PMID:15510212). BIOSYNTHESIS (cytosol->nucleus): GNE (Q9Y223 PTHR18964, bifunctional GO:0008761 epimerase + GO:0009384 ManNAc kinase, rate-limiting, CMP- Neu5Ac-feedback-inhibited; GNE myopathy/sialuria) -> NANS (Q9NR45 PTHR42966, GO:0047444 — the PHOSPHATE synthase EC 2.5.1.57, NOT GO:0050462; NANS-CDG) -> NANP (Q8TBE9 PTHR46470, GO:0050124 HAD phosphatase + Mg) -> CMAS (Q8NFW8 PTHR21485, GO:0008781 nuclear cytidylyltransferase making the CMP-Neu5Ac donor). TRANSPORT: SLC35A1 (P78382 PTHR10231, GO:0005456 Golgi CMP-Neu5Ac/CMP antiporter; SLC35A1-CDG/CDG-IIf). CATABOLISM: NEU1 (Q99519 PTHR10628, GO:0004308 lysosomal exo-alpha-sialidase in the CTSA/GLB1 complex; sialidosis) -> SLC17A5/sialin (Q9NRA2 PTHR11662:SF432, GO:0015538 lysosomal H+/sialic acid symporter; Salla disease/ISSD) -> NPL (Q9BXD5 PTHR12128, GO:0008747 cytosolic aldolase, Neu5Ac->ManNAc+pyruvate, recycling) or reactivation by CMAS. NANP is the characterized Neu5Ac-9-P phosphatase, but knockout cells keep making CMP-Neu5Ac through an unidentified alternative phosphatase (PMID:31121216). NAGK has been proposed as a second ManNAc kinase that could compensate for loss of GNE kinase activity, but the 2026 review calls this role unclear, so NAGK is not modeled as a member. The CMAS product CMP-Neu5Ac feedback-inhibits GNE (modelled as NEGATIVELY_REGULATES). ManNAc from NPL and ManNAc/sialic-acid supplementation can bypass upstream GNE/NANS/NPL defects therapeutically. GNPNAT1 (hexosamine/UDP-GlcNAc synthesis, upstream) and the sialyltransferases (downstream) are separate modules. GO term ids/labels verified against the local go.db.

Connections

GNE produces ManNAc-6-phosphate, the substrate condensed with PEP by NANS.
The Neu5Ac-9-phosphate made by NANS is dephosphorylated by NANP.
The free Neu5Ac released by NANP is activated by CMAS to CMP-Neu5Ac.
The CMP-Neu5Ac made by CMAS is imported into the Golgi by SLC35A1 for sialyltransferases.
CMP-Neu5Ac (the CMAS product) allosterically feedback-inhibits the GNE epimerase, matching flux to demand.
The free Neu5Ac released by lysosomal NEU1 is exported from the lysosome by SLC17A5.
Cytosolic free Neu5Ac exported by SLC17A5 is cleaved by NPL to ManNAc + pyruvate.
Salvaged free Neu5Ac exported by SLC17A5 can be reactivated by CMAS to CMP-Neu5Ac.
Part 1: ManNAc(-6-P) synthesis (bifunctional, rate-limiting)
UDP-GlcNAc 2-epimerase / ManNAc kinase (GNE)Reactionudpglcnac_to_mannac6p

Annotons

GNE: bifunctional UDP-GlcNAc 2-epimerase / ManNAc kinase
gne_activity
Participant: Family: GNE / bifunctional UDP-GlcNAc 2-epimerase-kinase family
Family:
GNE / bifunctional UDP-GlcNAc 2-epimerase-kinase familyPANTHER:PTHR18964
Representative Members: GNE (human)UniProtKB:Q9Y223

Function

UDP-N-acetylglucosamine 2-epimerase + N-acylmannosamine kinase activityGO:0008761
Substrates: UDP-N-acetyl-D-glucosamine ATP (kinase domain, GO:0009384)
Products: N-acetyl-D-mannosamine 6-phosphate (via ManNAc) UDP + ADP

Locations

cytosolGO:0005829

Makes ManNAc-6-phosphate from UDP-GlcNAc (epimerase + kinase).

Part 2: sialic acid synthase
N-acetylneuraminate-9-phosphate synthase (NANS)Reactionmannac6p_to_neu5ac9p

Annotons

NANS: sialic acid (Neu5Ac-9-P) synthase
nans_activity
Participant: Family: NANS / N-acetylneuraminate-9-phosphate synthase family
Family:
NANS / N-acetylneuraminate-9-phosphate synthase familyPANTHER:PTHR42966
Representative Members: NANS (human)UniProtKB:Q9NR45

Function

N-acylneuraminate-9-phosphate synthase activityGO:0047444
Substrates: N-acetyl-D-mannosamine 6-phosphate phosphoenolpyruvate (PEP)
Products: N-acetylneuraminate 9-phosphate (Neu5Ac-9-P) phosphate

Locations

cytosolGO:0005829

Condenses ManNAc-6-P + PEP to Neu5Ac-9-phosphate.

Part 3: Neu5Ac-9-P dephosphorylation
N-acylneuraminate-9-phosphatase (NANP)Reactionneu5ac9p_to_neu5ac

Annotons

NANP: Neu5Ac-9-phosphatase (HAD)
nanp_activity
Participant: Family: NANP / HAD N-acylneuraminate-9-phosphatase family
Family:
NANP / HAD N-acylneuraminate-9-phosphatase familyPANTHER:PTHR46470
Representative Members: NANP (human)UniProtKB:Q8TBE9

Function

N-acylneuraminate-9-phosphatase activityGO:0050124
Substrates: N-acetylneuraminate 9-phosphate (Mg2+)
Products: N-acetylneuraminate (free Neu5Ac) phosphate

Locations

cytosolGO:0005829

Dephosphorylates Neu5Ac-9-P to free Neu5Ac. NANP is the characterized enzyme for this step, but it is not essential for de novo Neu5Ac production in knockout cell lines, where an unidentified phosphatase bypasses it (PMID:31121216).

Part 4: sialic acid activation (CMP donor)
CMP-N-acetylneuraminate synthetase (CMAS)Reactionneu5ac_to_cmpneu5ac

Annotons

CMAS: CMP-sialic acid synthetase (nuclear)
cmas_activity
Participant: Family: CMAS / N-acylneuraminate cytidylyltransferase family
Family:
CMAS / N-acylneuraminate cytidylyltransferase familyPANTHER:PTHR21485
Representative Members: CMAS (human)UniProtKB:Q8NFW8

Function

N-acylneuraminate cytidylyltransferase activityGO:0008781
Substrates: N-acetylneuraminate (Neu5Ac) CTP
Products: CMP-N-acetylneuraminate (CMP-Neu5Ac, donor) diphosphate

Locations

nucleusGO:0005634

Activates Neu5Ac to CMP-Neu5Ac (sugar-nucleotide donor).

Part 5: Golgi import of the CMP-Neu5Ac donor
CMP-sialic acid transporter (SLC35A1)Reactioncmpneu5ac_golgi_import

Annotons

SLC35A1: CMP-Neu5Ac/CMP Golgi antiporter
slc35a1_activity
Participant: Family: SLC35A1 / nucleotide-sugar transporter family
Family:
SLC35A1 / nucleotide-sugar transporter familyPANTHER:PTHR10231
Representative Members: SLC35A1 (human)UniProtKB:P78382

Function

CMP-N-acetylneuraminate transmembrane transporter activityGO:0005456
Substrates: CMP-N-acetylneuraminate (cytosolic)
Products: CMP-N-acetylneuraminate (Golgi lumen; antiport for CMP)

Locations

Golgi membraneGO:0000139

Imports CMP-Neu5Ac into the Golgi lumen (antiport with CMP).

Part 6: lysosomal desialylation (catabolism)
Lysosomal sialidase (NEU1)Reactionlysosomal_desialylation

Annotons

NEU1: lysosomal exo-alpha-sialidase
neu1_activity
Participant: Family: NEU / sialidase (neuraminidase) family
Family:
NEU / sialidase (neuraminidase) familyPANTHER:PTHR10628
Representative Members: NEU1 (human)UniProtKB:Q99519

Function

exo-alpha-sialidase activityGO:0004308
Substrates: sialylated glycoproteins / glycolipids / oligosaccharides
Products: free N-acetylneuraminate + desialylated glycoconjugate

Locations

lysosomal lumenGO:0043202

Removes terminal sialic acid from glycoconjugates (lysosome).

Part 7: lysosomal export of free sialic acid
Lysosomal sialic acid transporter (SLC17A5, sialin)Reactionlysosomal_sialic_acid_export

Annotons

SLC17A5/sialin: lysosomal H+/sialic acid symporter
slc17a5_activity
Participant: Family: SLC17A5 / sialin subfamily of the SLC17 anion transporters
Family:
SLC17A5 / sialin subfamily of the SLC17 anion transportersPANTHER:PTHR11662:SF432
Representative Members: SLC17A5 (human)UniProtKB:Q9NRA2

Function

sialic acid:proton symporter activityGO:0015538
Substrates: free N-acetylneuraminate (lysosomal lumen) + H+
Products: free N-acetylneuraminate (cytosol) + H+

Locations

lysosomal membraneGO:0005765

Exports free sialic acid released by lysosomal sialidases to the cytosol, where it is reactivated by CMAS or cleaved by NPL. SLC17A5 is a multifunctional anion transporter, and only its lysosomal sialic acid efflux activity is modeled here. Deficiency causes the free sialic acid storage disorders (Salla disease and infantile sialic acid storage disease).

Part 8: free sialic acid cleavage / recycling
N-acetylneuraminate lyase (NPL)Reactionneu5ac_cleavage

Annotons

NPL: N-acetylneuraminate pyruvate lyase (aldolase)
npl_activity
Participant: Family: NPL / N-acetylneuraminate lyase family
Family:
NPL / N-acetylneuraminate lyase familyPANTHER:PTHR12128
Representative Members: NPL (human)UniProtKB:Q9BXD5

Function

N-acetylneuraminate lyase activityGO:0008747
Substrates: N-acetylneuraminate (free Neu5Ac)
Products: N-acetyl-D-mannosamine (ManNAc) pyruvate

Locations

cytosolGO:0005829

Cleaves free Neu5Ac to ManNAc + pyruvate (recycling).