SPTLC2 explained

Serine palmitoyltransferase, long chain base subunit 2, also known as SPTLC2, is a protein which in humans is encoded by the SPTLC2 gene.^{[1] [2] [3]} SPTLC2 belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.

Function

SPTLC2 encodes a long chain base subunit of serine palmitoyltransferase (SPT). The heterodimer formed with LCB1/SPTLC1 constitutes the catalytic core. It catalyzes the pyridoxal 5'-phosphate dependent condensation of L-serine with an acyl-CoA thioester to yield an amino alcohol. The composition of the SPT complex determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC2-SPTSSB complex displays a preference for C18-CoA substrate.

The SPT complex synthesizes molecules used in various biological processes. For example, sphingosine, an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, can be phosphorylated via sphingosine kinase. The resulting sphingosine-1-phosphate is a potent signaling lipid. Sphingosine is also a substrate for the synthesis of various other molecules including, ceramides, sphingomyelin, cerebrosides and globosides.

Epidermal ceramides are critical for normal skin barrier function and SPTLC2 is differentially expressed across body sites to regulate epidermal ceramide composition. In particular, SPTLC2 is upregulated in acral granular layer keratinocytes.^[4]

Tissue distribution

SPTLC2 is widely expressed in all tissues.

Clinical significance

Mutations in SPTLC2 were identified in patients with hereditary sensory neuropathy type I.^[5]

In response to IL-17A and TNF, SPTLC2 is highly upregulated in psoriasis and is likely responsible for some of the epidermal ceramide alterations seen in psoriasis plaques.

Alternatively spliced variants encoding different isoforms of SPTLC2 have been identified.

SPTLC2 expression is highly increased at the protein level in brains of patients with Alzheimer's disease. No changes are observed at the mRNA level.^[6]

Further reading

• Takeda J, Yano H, Eng S, Zeng Y, Bell GI . A molecular inventory of human pancreatic islets: sequence analysis of 1000 cDNA clones . Human Molecular Genetics . 2 . 11 . 1793–1798 . November 1993 . 7506601 . 10.1093/hmg/2.11.1793 .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . 6 . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–828 . September 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Nagiec MM, Lester RL, Dickson RC . Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase . Gene . 177 . 1–2 . 237–241 . October 1996 . 8921873 . 10.1016/0378-1119(96)00309-5 .
• Weiss B, Stoffel W . Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis . European Journal of Biochemistry . 249 . 1 . 239–247 . October 1997 . 9363775 . 10.1111/j.1432-1033.1997.00239.x . free .
• Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro . DNA Research . 5 . 1 . 31–39 . February 1998 . 9628581 . 10.1093/dnares/5.1.31 . free . 10.1.1.610.1181 .
• Hanada K, Hara T, Nishijima M . Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques . The Journal of Biological Chemistry . 275 . 12 . 8409–8415 . March 2000 . 10722674 . 10.1074/jbc.275.12.8409 . free .
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ . 6 . Shotgun sequencing of the human transcriptome with ORF expressed sequence tags . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3491–3496 . March 2000 . 10737800 . 16267 . 10.1073/pnas.97.7.3491 . free . 2000PNAS...97.3491D .
• Dawkins JL, Brahmbhatt S, Auer-Grumbach M, Wagner K, Hartung HP, Verhoeven K, Timmerman V, De Jonghe P, Kennerson M, LeGuern E, Nicholson GA . 6 . Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy . Neuromuscular Disorders . 12 . 7–8 . 656–658 . October 2002 . 12207934 . 10.1016/S0960-8966(02)00015-9 . 1248860 .
• Stachowitz S, Alessandrini F, Abeck D, Ring J, Behrendt H . Permeability barrier disruption increases the level of serine palmitoyltransferase in human epidermis . The Journal of Investigative Dermatology . 119 . 5 . 1048–1052 . November 2002 . 12445191 . 10.1046/j.1523-1747.2002.19524.x . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . Huda Zoghbi . 2005Natur.437.1173R .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–648 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . free .
• Chen M, Han G, Dietrich CR, Dunn TM, Cahoon EB . The essential nature of sphingolipids in plants as revealed by the functional identification and characterization of the Arabidopsis LCB1 subunit of serine palmitoyltransferase . The Plant Cell . 18 . 12 . 3576–3593 . December 2006 . 17194770 . 1785403 . 10.1105/tpc.105.040774 .
• Hornemann T, Wei Y, von Eckardstein A . Is the mammalian serine palmitoyltransferase a high-molecular-mass complex? . The Biochemical Journal . 405 . 1 . 157–164 . July 2007 . 17331073 . 1925250 . 10.1042/BJ20070025 .

Notes and References

1. Web site: Entrez Gene: SPTLC2 serine palmitoyltransferase, long chain base subunit 2.
2. Nagiec MM, Lester RL, Dickson RC . Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase . Gene . 177 . 1–2 . 237–241 . October 1996 . 8921873 . 10.1016/0378-1119(96)00309-5 .
3. Weiss B, Stoffel W . Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis . European Journal of Biochemistry . 249 . 1 . 239–247 . October 1997 . 9363775 . 10.1111/j.1432-1033.1997.00239.x . free .
4. Merleev AA, Le ST, Alexanian C, Toussi A, Xie Y, Marusina AI, Watkins SM, Patel F, Billi AC, Wiedemann J, Izumiya Y, Kumar A, Uppala R, Kahlenberg JM, Liu FT, Adamopoulos IE, Wang EA, Ma C, Cheng MY, Xiong H, Kirane A, Luxardi G, Andersen B, Tsoi LC, Lebrilla CB, Gudjonsson JE, Maverakis E . 6 . Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes . JCI Insight . 7 . 16 . e159762 . August 2022 . 35900871 . 9462509 . 10.1172/jci.insight.159762 .
5. Murphy SM, Ernst D, Wei Y, Laurà M, Liu YT, Polke J, Blake J, Winer J, Houlden H, Hornemann T, Reilly MM . 6 . Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2 . Neurology . 80 . 23 . 2106–2111 . June 2013 . 23658386 . 3716354 . 10.1212/WNL.0b013e318295d789 .
6. Geekiyanage H, Chan C . MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer's disease . The Journal of Neuroscience . 31 . 41 . 14820–14830 . October 2011 . 21994399 . 3200297 . 10.1523/JNEUROSCI.3883-11.2011 .