The structure of serine palmitoyltransferase; Gateway to sphingolipid biosynthesis

Sphingolipid biosynthesis commences with the condensation of L-serine and palmitoyl-CoA to produce 3-ketodihydrosphingosine (KDS). This reaction is catalysed by the PLP-dependent enzyme serine palmitoyltransferase (SPT; EC 2.3.1.50), which is a membrane-bound heterodirner (SPT1 SPT2) in eukaryotes such as humans and yeast and a cytoplasmic homodimer in the Gram-negative bacterium Sphingomonas pauchnobilis. Unusually, the outer membrane of S. paucimobilis contains glycosphingolipid (GSL) instead of lipopolysaccharide (LPS), and SPT catalyses the first crystal structure of the holo-form of S. paucimobilis SPT at 1.3 angstrom resolution. enzyme is a symmetrical homodimer with two active sites and monomeric tertiary structure consisting of three domains. The PLP cofactor is bound covalently to a lysine residue (Lys265) as an internal aldimine/ Schiff base and the active site is composed of residues from both subunits, located at the bottom of a deep cleft. Models of the human SPT1/SPT2 heterodimer were generated from the bacterial structure by bioinformatics analysis. Mutations in the human SPT1-encoding subunit have been shown to cause a neuropathological disease known as hereditary sensory and autonomic neuropathy type I (HSAN1). Our models provide an understanding of how these mutations may affect the activity of the enzyme. (c) 2007 Elsevier Ltd. All rights reserved.