Pathway: CMP-N-acetylneuraminate biosynthesis I (eukaryotes)

General Background Sialic acids are a family of polyhydroxylated α-keto acids that contain nine carbon atoms. Most sialic acids are derivatives of |FRAME: N-ACETYLNEURAMINATE|, or |FRAME: CPD-10734| (KDN). |FRAME: N-ACETYLNEURAMINATE| is the most common sialic acid in humans (this pathway). Their core structures can be modified at the hydroxyl groups, lactonized, or hydroxylated at the acetamido group, generating many derivatives. |FRAME: CPD-262| is a derivative of |FRAME: CMP-N-ACETYL-NEURAMINATE| (see pathway |FRAME: PWY-6144|). Reviewed in |CITS: [15888312] [16897172]|. Sialic acids are usually the terminal sugar residue in the glycan chains of human glycoconjugates (mostly glycoproteins and glycolipids, but also proteoglycans and glycosylphosphatidylinositol anchors). They function in mediating cellular recognition and adhesion events for many important processes such as development, the immune and inflammatory responses, and oncogenesis. About This Pathway |FRAME: N-ACETYLNEURAMINATE| biosynthesis begins with the conversion of |FRAME: UDP-N-ACETYL-D-GLUCOSAMINE| to |FRAME: N-ACETYL-D-MANNOSAMINE|. This reaction involves both an inversion of stereochemistry at C-2 of the sugar moiety and hydrolysis of the glycosidic phosphate bond. |FRAME: N-ACETYL-D-MANNOSAMINE| is then phosphorylated to its 6-phosphate derivative. Condensation with |FRAME: PHOSPHO-ENOL-PYRUVATE| then forms |FRAME: N-ACETYL-NEURAMINATE-9P|, a distinctive biosynthetic step. After dephosphorylation to |FRAME: N-ACETYLNEURAMINATE|, |FRAME: CTP| is used to generate the activated form of sialic acid, |FRAME: CMP-N-ACETYL-NEURAMINATE|. This step is in contrast to activation of other monosaccharides, the activated forms of which use |FRAME: URIDINE| or |FRAME: GUANINE| dinucleotides. The |FRAME: CMP|-activated form is the sialic acid donor for glycoconjugates. Reviewed in |CITS: [15888312] [16897172]|. |FRAME: N-ACETYLNEURAMINATE| is biosynthesized in the cytosol. However, its |FRAME: CMP| derivative, |FRAME: CMP-N-ACETYL-NEURAMINATE|, is formed in the nucleus, enters the cytosol and is then transported into the golgi apparatus by a golgi CMP-sialic acid transporter |CITS: [18713811] [16923816] [8755516]|. In the golgi lumen |FRAME: CMP-N-ACETYL-NEURAMINATE| serves as a sialic acid donor for sialyltransferases in the formation of glycoconjugates. For examples of sialyltransferases see EC 2.4.99.1 through EC 2.4.99.11. |FRAME: CMP-N-ACETYL-NEURAMINATE| can also be hydroxylated to |FRAME: CPD-262| by the |FRAME: CPLX-7746| and transferred to glycoconjugates (as shown in the pathway link). Reviewed in |CITS: [15888312] [16897172]| and |CITS: [18568399]|. The first two reactions are catalyzed by a bifunctinal enzyme that catalyzes the rate-limiting steps in sialic acid biosynthesis. The supply of |FRAME: N-ACETYLNEURAMINATE| is regulated through feedback inhibition by |FRAME: CMP-N-ACETYL-NEURAMINATE| |CITS: [9305887]|. Reviewed in |CITS: [15888312] [16897172]| and |CITS: [18568399]|.