Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism.
The first step in the biosynthesis of sphingolipids is the condensation of serine and palmitoyl CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) to produce 3-ketodihydrosphingosine (KDS). This review focuses on recent advances in the biochemistry and molecular biology of SPT. SPT belongs to a family of pyridoxal 5'-phosphate (PLP)-dependent alpha-oxoamine synthases (POAS). Mammalian SPT is a heterodimer of 53-kDa LCB1 and 63-kDa LCB2 subunits, both of which are bound to the endoplasmic reticulum (ER) most likely with the type I topology, whereas other members of the POAS family are soluble homodimer enzymes. LCB2 appears to be unstable unless it is associated with LCB1. Potent inhibitors of SPT structurally resemble an intermediate in a probable multistep reaction mechanism for SPT. Although SPT is a housekeeping enzyme, its activity is regulated transcriptionally and post-transcriptionally, and its up-regulation is suggested to play a role in apoptosis induced by certain types of stress. Specific missense mutations in the human LCB1 gene cause hereditary sensory neuropathy type I, an autosomal dominantly inherited disease, and these mutations confer dominant-negative effects on SPT activity.
Hanada
Kentaro
K
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku, Tokyo 162-8640, Japan. hanak@nih.go.jp
D000217:Acyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D005544:Forecasting; D005786:Gene Expression Regulation; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
D013107:Sphingolipids; D000217:Acyltransferases; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase