Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewSerine palmitoyltransferase, a key enzyme of sphingolipid metabolism
Introduction
Sphingolipids are defined as lipids containing sphingoid bases (1,3-dihydroxy-2-amino-alkane and its derivatives) as a structural backbone. Sphingolipids are ubiquitous constituents of membrane lipids in eukaryotes, and are also distributed to some prokaryotes. Since Johann L.W. Thudichum first described the existence of biological compounds containing a previously unrecognized aliphatic alkaloid called “sphingosine” in the brain more than 100 years ago, studies on the structure, distribution, and metabolism of sphingolipids have advanced greatly [1], [2]. In the past decade, sphingolipid metabolites have been revealed to modulate various cellular events including proliferation, differentiation, and apoptosis [3], [4], [5], and sphingolipids, along with cholesterol, have been shown to be required for the formation of detergent-resistant membrane microdomains [6], [7], [8], which are implicated in signal transduction and membrane trafficking [9]. In addition, crucial roles for cutaneous ceramides in the skin barrier function have been recognized [10]. Accordingly, the molecular mechanisms underlying sphingolipid metabolism have attracted much attention.
The first step involved in sphingolipid biosynthesis is the condensation of serine and palmitoyl CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) [EC 2.3.1.50] to produce 3-ketodihydrosphingosine (KDS). SPT is suggested to be a key enzyme for the regulation of sphingolipid levels in cells because regulation of sphingolipid synthesis at the SPT step prevents a harmful accumulation of metabolic sphingolipid-intermediates including sphingoid bases and ceramide, while repression of other anabolic steps in the sphingolipid synthetic pathway may cause the intermediates to accumulate. This review summarizes recent advances in the biochemistry and molecular biology of SPT, mainly focusing on the mammalian SPT enzyme.
Section snippets
Structure and biosynthesis of sphingolipids
There are three major types of sphingoid bases (Fig. 1). Sphingosine is the principal sphingoid base of sphingolipids in mammalian cells, and dihydrosphingosine is the second most abundant type. Phytosphingosine (4-hydroxydihydrosphingosine) is the principal sphingoid base in plants and fungi, although some tissues including the kidney and stomach in mammals also have considerable amounts of phytosphingosine-containing sphingolipids. For natural sphingoid bases, the alkyl chain length is
Early history of SPT
In the early 1950s, chemical analysis of metabolically labeled sphingolipids suggested that C-3 to C-18 of sphingosine were derived from palmitic acid [16], but that C-1 and C-2 were from serine [17]. Based on these results, Sprinson and Coulon [17] hypothesized that the condensation of acyl CoA and serine produced a 3-keto derivative, and Weiss [18] later proposed a Schiff's base-dependent mechanism for the formation of a 3-keto derivative from serine and palmitoyl CoA. At that time, the first
Regulation of SPT activity
Consistent with the ubiquitous expression of sphingolipids in mammalian cells, SPT activity is detected in many types of tissue and cell preparations as summarized in a previous review [73]. In addition, mRNA for SPT subunits is ubiquitously expressed in various tissues, although the mRNA levels vary depending on tissue type [33], [34]. The level of SPT activity also varies among different types of tissues and cells. SPT activity levels are significantly higher in rat lung and kidney microsomes
SPT and a genetic disease
Abnormalities of the SPT enzyme cause clinical disorders, although a complete lack of SPT activity is predicted to be embryonic lethal. Hereditary sensory neuropathy type I (HSN1) is a dominantly inherited disease involving the progressive degeneration of lower limb sensory and autonomic neurons [118]. HSN1 is a genetically heterogeneous disease, and at least three gene variants are reported. It has recently been revealed that the genetic defect in the HSN1 families linked to the chromosome
Future directions
Great progress in research on SPT has been made in the past decade as summarized in this review. Nevertheless, more studies are needed to elucidate the molecular mechanisms underlying the function and regulation of SPT. For example, determination of the tertiary structure of this enzyme will be required to elucidate how the two subunits form a complex. Because no report has so far demonstrated direct inhibition of SPT activity by sphingolipid metabolites in vitro, assay conditions that mimic
Acknowledgments
I thank Dr. Masahiro Nishijima, Dr. Yuzuru Akamatsu, and all other present and past co-workers for invaluable contributions to studies of the SPT enzyme. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI#12140206 and #12680610), and by Terumo Life Science Foundation.
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