7yj1

Structural highlights

Disease

SPTC2_HUMAN Hereditary sensory and autonomic neuropathy type 1. The disease is caused by variants affecting the gene represented in this entry. SPTLC2 disease mutations cause a shift in the substrate specificity of SPT resulting in the alternative use of L-alanine and L-glycine over its canonical substrate L-serine. This leads to the production of 1-deoxysphingolipids that cannot be correctly metabolized (PubMed:23658386).^{[1] [2]}

Function

SPTC2_HUMAN Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases (PubMed:19416851, PubMed:19648650, PubMed:20504773, PubMed:20920666). The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core (PubMed:19416851). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference (PubMed:19416851). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA (PubMed:19416851, PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (PubMed:19416851, PubMed:19648650). Crucial for adipogenesis (By similarity).[UniProtKB:P97363]^{[3] [4] [5] [6]}

See Also

• Serine palmitoyltransferase 3D structures

References

1. ↑ Murphy SM, Ernst D, Wei Y, Laurà M, Liu YT, Polke J, Blake J, Winer J, Houlden H, Hornemann T, Reilly MM. Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology. 2013 Jun 4;80(23):2106-11. PMID:23658386 doi:10.1212/WNL.0b013e318295d789
2. ↑ Suriyanarayanan S, Auranen M, Toppila J, Paetau A, Shcherbii M, Palin E, Wei Y, Lohioja T, Schlotter-Weigel B, Schön U, Abicht A, Rautenstrauss B, Tyynismaa H, Walter MC, Hornemann T, Ylikallio E. The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy. Neuromolecular Med. 2016 Mar;18(1):81-90. PMID:26573920 doi:10.1007/s12017-015-8379-1
3. ↑ Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM, Dunn TM. Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A. 2009 May 19;106(20):8186-91. PMID:19416851 doi:10.1073/pnas.0811269106
4. ↑ Hornemann T, Penno A, Rütti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L, von Eckardstein A. The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem. 2009 Sep 25;284(39):26322-30. PMID:19648650 doi:10.1074/jbc.M109.023192
5. ↑ Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM. A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity. J Biol Chem. 2010 Jul 23;285(30):22846-52. PMID:20504773 doi:10.1074/jbc.M110.122259
6. ↑ Rotthier A, Auer-Grumbach M, Janssens K, Baets J, Penno A, Almeida-Souza L, Van Hoof K, Jacobs A, De Vriendt E, Schlotter-Weigel B, Löscher W, Vondráček P, Seeman P, De Jonghe P, Van Dijck P, Jordanova A, Hornemann T, Timmerman V. Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet. 2010 Oct 8;87(4):513-22. PMID:20920666 doi:10.1016/j.ajhg.2010.09.010