SPTLC complexes transfer acyl-CoA onto serine

Stable Identifier
R-HSA-428127
Type
Reaction [transition]
Species
Homo sapiens
Compartment
Synonyms
acyl-CoA + serine => 3-ketosphingoid + CoASH + CO2
ReviewStatus
5/5
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SPTLC (serine palmitoyltransferase) enzyme complexes associated with the endoplasmic reticulum membrane catalyze the reaction of acyl-CoA and serine to form a 3-ketosphingoid. Quantitatively, the most common ligand is palmitoyl-CoA (C16), but different isoforms of the complexes have specific activity toward the C12, C14, and C18 species (Han et al., 2009; Suzuki et al., 2022). SPTLC2 and SPTLC3 polypeptides exhibit enzyme activity when either is complexed with SPTLC1. SPTLC1 and 2 are abundant and widely expressed in human tissues, while SPTLC3 is expressed only in a smaller group of tissues and at variable levels. Analyses of complexes from cultured human cells and placenta suggested that the SPTLC heterodimers might associate with larger complexes (Hanada et al., 2000; Weiss and Stoffel, 1997; Hornemann et al. 2006, 2007; reviewed by Ikushiro & Hayashi, 2011; Lowther et al., 2012). Two novel small subunits (SPTSSA and SPTSSB) were identified, both of which enhance SPTLC activity >10-fold when bound to either of the SPTLC heterodimers (Han et al. 2009). Orosomucoid (ORM) proteins, first identified in yeast, associate with and negatively regulate SPTLC activity (Breslow et al. 2010; Han et al. 2010). The three human ORM proteins similarly bind and negatively regulate SPTLC activity (Breslow et al., 2010; reviewed by Davis et al., 2018). In particular, dysregulation of SPT activity by ORML3 appears to be involved with forms of obesity (reviewed by Brown & Spiegel, 2023). In serine deficiency, SPTLC transfers acyl-CoA onto alanine, and the resulting 1-deoxysphingoids ultimately get processed to 1-deoxyceramides (reviewed by Duan & Merrill, 2015).
Literature References
PubMed ID Title Journal Year
21315853 Mechanistic enzymology of serine palmitoyltransferase

Hayashi, H, Ikushiro, H

Biochim Biophys Acta 2011
22616865 Structural, mechanistic and regulatory studies of serine palmitoyltransferase

Naismith, JH, Campopiano, DJ, Dunn, TM, Lowther, J

Biochem Soc Trans 2012
17023427 Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase

Richard, S, Wei, Y, Rutti, MF, Hornemann, T, von Eckardstein, A

J Biol Chem 2006
9363775 Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis

Stoffel, W, Weiss, B

Eur J Biochem 1997
20212121 Orm1 and Orm2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control

Schneiter, R, Chang, A, Han, S, Lone, MA

Proc. Natl. Acad. Sci. U.S.A. 2010
17331073 Is the mammalian serine palmitoyltransferase a high-molecular-mass complex?

Wei, Y, Hornemann, T, von Eckardstein, A

Biochem J 2007
20182505 Orm family proteins mediate sphingolipid homeostasis

Aebersold, R, Bodenmiller, B, Weissman, JS, Collins, SR, Simons, K, Shevchenko, A, Ejsing, CS, Breslow, DK

Nature 2010
19416851 Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities

Gupta, SD, Harmon, JM, Brown, RH, Eichler, F, Han, G, Niranjanakumari, S, Moitra, P, Gable, K, Dunn, TM

Proc. Natl. Acad. Sci. U.S.A. 2009
10722674 Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques

Hara, T, Hanada, K, Nishijima, M

J Biol Chem 2000
37003301 ORMDL in metabolic health and disease

Brown, RDR, Spiegel, S

Pharmacol Ther 2023
35654151 Whole picture of human stratum corneum ceramides, including the chain-length diversity of long-chain bases

Ohno, Y, Kihara, A, Suzuki, M

J Lipid Res 2022
25947379 1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma

Merrill, AH, Duan, J

J Biol Chem 2015
30193828 Orm/ORMDL proteins: Gate guardians and master regulators

Kannan, M, Davis, D, Wattenberg, B

Adv Biol Regul 2018
Participants
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Catalyst Activity

serine C-palmitoyltransferase activity of SPTLC complexes [endoplasmic reticulum membrane]

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