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, 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) and an NPL-related myopathy — several of which are amenable to ManNAc / sialic-acid supplementation.