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词条 Serine C-palmitoyltransferase
释义

  1. Nomenclature

  2. Structure

  3. Mechanism

  4. Isoforms

  5. Clinical significance

  6. Species distribution

  7. References

{{enzyme
| Name = serine C-palmitoyltransferase
| EC_number = 2.3.1.50
| CAS_number = 62213-50-7
| IUBMB_EC_number = 2/3/1/50
| GO_code = 0004758
| image =
| width =
| caption =
}}{{Infobox protein
| Name = Serine palmitoyltransferase
| caption = Crystallographic structure of serine palmitoyltransferase from S. paucimobilis. The cofactor PLP is visible in the center.[1]
| image = SPT 2jg2.png
| HGNCid =
| Symbol = SPT1
| AltSymbols =
| EntrezGene =
| OMIM =
| RefSeq =
| UniProt = Q93UV0
| PDB = 2JG2
| ECnumber = 2.3.1.50
| Chromosome =
| Arm =
| Band =
| LocusSupplementaryData =
}}{{infobox protein | Name = serine palmitoyltransferase, long chain base subunit 1 | caption = | image = | width = | HGNCid = 11277 | Symbol = SPTLC1 | AltSymbols = HSN1 | EntrezGene = 10558 | OMIM = 605712 | RefSeq = NM_006415 | UniProt = O15269 | PDB = | ECnumber = 2.3.1.50 | Chromosome = 9 | Arm = q | Band = 22.31 | LocusSupplementaryData = }}{{infobox protein | Name = serine palmitoyltransferase, long chain base subunit 2 | caption = | image = | width = | HGNCid = 11278 | Symbol = SPTLC2 | AltSymbols = | EntrezGene = 9517 | OMIM = 605713 | RefSeq = NM_004863 | UniProt = O15270 | PDB = | ECnumber = 2.3.1.50 | Chromosome = 14 | Arm = q | Band = 24.3 | LocusSupplementaryData = }}{{infobox protein | Name = serine palmitoyltransferase, long chain base subunit 3 | caption = | image = | width = | HGNCid = 16253 | Symbol = SPTLC3 | AltSymbols = C20orf38, SPTLC2L | EntrezGene = 55304 | OMIM = 611120 | RefSeq = NM_018327 | UniProt = Q9NUV7 | PDB = | ECnumber = 2.3.1.50 | Chromosome = 20 | Arm = p | Band = 12.1 | LocusSupplementaryData = }}

In enzymology, a serine C-palmitoyltransferase ({{EC number|2.3.1.50}}) is an enzyme that catalyzes the chemical reaction:[2][3]

palmitoyl-CoA + L-serine CoA + 3-dehydro-D-sphinganine + CO2

Thus, the two substrates of this enzyme are palmitoyl-CoA and L-serine, whereas its 3 products are CoA, 3-dehydro-D-sphinganine, and CO2.[4][5] This reaction is a key step in the biosynthesis of sphingosine which is a precursor of many other sphingolipids.[3]

This enzyme participates in sphingolipid metabolism. It employs one cofactor, pyridoxal phosphate.

Nomenclature

This enzyme belongs to the family of transferases, specifically those acyltransferases transferring groups other than aminoacyl groups. The systematic name of this enzyme class is palmitoyl-CoA:L-serine C-palmitoyltransferase (decarboxylating). Other names in common use include:

  • serine palmitoyltransferase,
  • SPT, 3-oxosphinganine synthetase, and
  • acyl-CoA:serine C-2 acyltransferase decarboxylating.

Structure

Serine C-palmitoyltransferase is a member of the AOS (a-oxoamine synthase) family of PLP-dependent enzymes, which catalyse the condensation of amino acids and acyl-CoA thioester substrates.[6] The human enzyme is a heterodimer consisting of two monomeric subunits known as long chain base 1 and 2 (LCB1/2) encoded by separate genes.[1] The active site of LCB2 contains lysine and other key catalytic residues that are not present in LCB1, which does not participate in catalysis but is nevertheless required for the synthesis and stability of the enzyme.[7]

As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes {{PDB link|2JG2}} and {{PDB link|2JGT}}.[1]

Mechanism

The PLP (pyridoxal 5′-phosphate)-dependent serine C-palmitoyltransferase carries out the first enzymatic step of de novo sphingolipid biosynthesis. The enzyme catalyses a Claisen-like condensation between L-serine and an acyl-CoA thioester (CoASH) substrate (typically C16-palmitoyl) or an acyl-ACP (acyl-carrier protein) thioester substrate, to form 3-ketodihydrosphingosine. Initially PLP cofactor is bound to the active-site lysine via a Schiff base to form the holo-form or internal aldimine of the enzyme. The amine group of L-serine then attacks and displaces the lysine bound to PLP, forming the external aldimine intermediate. Subsequently, deprotonation occurs at the Cα of serine, forming the quinonoid intermediate that attacks the incoming thioester substrate. Following decarboxylation and lysine attack, the product 3-ketodihydrosphingosine is released and catalytically active PLP is reform. This condensation reaction forms the sphingoid base or long-chain base found in all subsequent intermediate sphingolipids and complex sphingolipids in the organism.[3]

Isoforms

A variety of different serine C-palmitoyltransferase isoforms exist across different species. Unlike in eukaryotes, where the enzyme is heterodimeric and membrane bound, bacterial enzymes are homodimers and cytoplasmic. Studies of the isoform of the enzyme found in the Gram-negative bacterium S. paucimobilis were the first to elucidate the structure of the enzyme, revealing that PLP cofactor is held in place by several active site residues including Lys265 and His159.[8] Specifically, the S. paucimobilis isoform features an active-site arginine residue (Arg378) that plays a key role in stabilizing the carboxy moiety of the PLP-L-serine external aldimine intermediate. Similar arginine residues in enzyme homologues (Arg370, Arg390) play analogous roles.[9]

Other homologues, such as in Sphingobacterium multivorum, feature the carboxy moiety bound to serine and methionine residues via water in place of arginine.[10] Certain enzyme homologues, such as in S. multivorum as well as B. stolpii, are found to be associated with the inner cell membrane, thus resembling the eukaryotic enzymes.[11] The B. stolpii homologue also features substrate inhibition by palmitoyl-CoA, a feature shared by the yeast and mammalian homologues.[12][13][14]

Clinical significance

HSAN1 (hereditary sensory and autonomic neuropathy type 1) is a genetic disorder caused by mutations in either one of SPTLC1 or SPTLC2, genes encoding the two heterodimeric subunits of the eukaryotic serine C-palmitoyltransferase enzyme.[15][16][17] These mutations have been shown to alter active site specificity, specifically by enhancing the ability of the enzyme to condense L-alanine with the palmitoyl-CoA substrate.[18] This is consistent with elevated levels of deoxysphingoid bases formed by the condensation of alanine with palmitoyl-CoA observed in HSAN1 patients.[19]

Species distribution

Serine C-palmitoyltransferase is expressed in a large number of species from bacteria to humans. The bacterial enzyme is a water-soluble homodimer[2] whereas in eukaryotes the enzyme is a heterodimer which is anchored to the endoplasmic reticulum.[3] Humans and other mammals express three paralogous subunits SPTLC1, SPTLC2, and SPTLC3. It was originally proposed that the functional human enzyme is a heterodimer between a SPTLC1 subunit and a second subunit which is either SPTLC2 or SPTLC3.[20] However more recent data suggest that the enzyme may exist as a larger complex, possibly an octamer, comprising all three subunits.[21]

References

1. ^1 2 {{cite journal | vauthors = Yard BA, Carter LG, Johnson KA, Overton IM, Dorward M, Liu H, McMahon SA, Oke M, Puech D, Barton GJ, Naismith JH, Campopiano DJ | title = The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis | journal = Journal of Molecular Biology | volume = 370 | issue = 5 | pages = 870–86 | date = July 2007 | pmid = 17559874 | doi = 10.1016/j.jmb.2007.04.086 }}
2. ^1 {{cite journal | vauthors = Ikushiro H, Hayashi H, Kagamiyama H | title = Bacterial serine palmitoyltransferase: a water-soluble homodimeric prototype of the eukaryotic enzyme | journal = Biochimica et Biophysica Acta | volume = 1647 | issue = 1–2 | pages = 116–20 | date = April 2003 | pmid = 12686119 | doi = 10.1016/S1570-9639(03)00074-8 }}
3. ^1 2 3 {{cite journal | vauthors = Hanada K | title = Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism | journal = Biochimica et Biophysica Acta | volume = 1632 | issue = 1–3 | pages = 16–30 | date = June 2003 | pmid = 12782147 | doi = 10.1016/S1388-1981(03)00059-3 }}
4. ^{{cite journal | vauthors = Brady RN, Di Mari SJ, Snell EE | title = Biosynthesis of sphingolipid bases. 3. Isolation and characterization of ketonic intermediates in the synthesis of sphingosine and dihydrosphingosine by cell-free extracts of Hansenula ciferri | journal = The Journal of Biological Chemistry | volume = 244 | issue = 2 | pages = 491–6 | date = January 1969 | pmid = 4388074 | doi = | url = http://www.jbc.org/cgi/content/abstract/244/2/491 }}
5. ^{{cite journal | vauthors = Stoffel W, LeKim D, Sticht G | title = Biosynthesis of dihydrosphingosine in vitro | journal = Hoppe-Seyler's Zeitschrift für Physiologische Chemie | volume = 349 | issue = 5 | pages = 664–70 | date = May 1968 | pmid = 4386961 | doi = 10.1515/bchm2.1968.349.1.664 }}
6. ^{{cite journal | vauthors = Eliot AC, Kirsch JF | title = Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations | journal = Annual Review of Biochemistry | volume = 73 | issue = | pages = 383–415 | year = 2004 | pmid = 15189147 | doi = 10.1146/annurev.biochem.73.011303.074021 }}
7. ^{{cite journal | vauthors = Han G, Gable K, Yan L, Natarajan M, Krishnamurthy J, Gupta SD, Borovitskaya A, Harmon JM, Dunn TM | title = The topology of the Lcb1p subunit of yeast serine palmitoyltransferase | journal = The Journal of Biological Chemistry | volume = 279 | issue = 51 | pages = 53707–16 | date = December 2004 | pmid = 15485854 | doi = 10.1074/jbc.M410014200 }}
8. ^{{cite journal | vauthors = Shiraiwa Y, Ikushiro H, Hayashi H | title = Multifunctional role of His159in the catalytic reaction of serine palmitoyltransferase | journal = The Journal of Biological Chemistry | volume = 284 | issue = 23 | pages = 15487–95 | date = June 2009 | pmid = 19346561 | pmc = 2786316 | doi = 10.1074/jbc.M808916200 }}
9. ^{{cite journal | vauthors = Lowther J, Charmier G, Raman MC, Ikushiro H, Hayashi H, Campopiano DJ | title = Role of a conserved arginine residue during catalysis in serine palmitoyltransferase | journal = FEBS Letters | volume = 585 | issue = 12 | pages = 1729–34 | date = June 2011 | pmid = 21514297 | doi = 10.1016/j.febslet.2011.04.013 }}
10. ^{{cite journal | vauthors = Ikushiro H, Islam MM, Okamoto A, Hoseki J, Murakawa T, Fujii S, Miyahara I, Hayashi H | title = Structural insights into the enzymatic mechanism of serine palmitoyltransferase from Sphingobacterium multivorum | journal = Journal of Biochemistry | volume = 146 | issue = 4 | pages = 549–62 | date = October 2009 | pmid = 19564159 | doi = 10.1093/jb/mvp100 }}
11. ^{{cite journal | vauthors = Ikushiro H, Islam MM, Tojo H, Hayashi H | title = Molecular characterization of membrane-associated soluble serine palmitoyltransferases from Sphingobacterium multivorum and Bdellovibrio stolpii | journal = Journal of Bacteriology | volume = 189 | issue = 15 | pages = 5749–61 | date = August 2007 | pmid = 17557831 | pmc = 1951810 | doi = 10.1128/JB.00194-07 }}
12. ^{{cite journal | vauthors = Gable K, Slife H, Bacikova D, Monaghan E, Dunn TM | title = Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity | journal = The Journal of Biological Chemistry | volume = 275 | issue = 11 | pages = 7597–603 | date = March 2000 | pmid = 10713067 | doi = 10.1074/jbc.275.11.7597 }}
13. ^{{cite journal | vauthors = Hanada K, Hara T, Nishijima M | title = Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques | journal = The Journal of Biological Chemistry | volume = 275 | issue = 12 | pages = 8409–15 | date = March 2000 | pmid = 10722674 | doi = 10.1074/jbc.275.12.8409 }}
14. ^{{cite journal | vauthors = Lara PN, Moon J, Redman MW, Semrad TJ, Kelly K, Allen JW, Gitlitz BJ, Mack PC, Gandara DR | title = Relevance of platinum-sensitivity status in relapsed/refractory extensive-stage small-cell lung cancer in the modern era: a patient-level analysis of southwest oncology group trials | journal = Journal of Thoracic Oncology | volume = 10 | issue = 1 | pages = 110–5 | date = January 2015 | pmid = 25490004 | pmc = 4320001 | doi = 10.1097/JTO.0000000000000385 }}
15. ^{{cite journal | vauthors = Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH | title = SPTLC1 is mutated in hereditary sensory neuropathy, type 1 | journal = Nature Genetics | volume = 27 | issue = 3 | pages = 261–2 | date = March 2001 | pmid = 11242106 | doi = 10.1038/85817 }}
16. ^{{cite journal | vauthors = Gable K, Han G, Monaghan E, Bacikova D, Natarajan M, Williams R, Dunn TM | title = Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 12 | pages = 10194–200 | date = March 2002 | pmid = 11781309 | doi = 10.1074/jbc.M107873200 }}
17. ^{{cite journal | vauthors = 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 | title = Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I | journal = American Journal of Human Genetics | volume = 87 | issue = 4 | pages = 513–22 | date = October 2010 | pmid = 20920666 | pmc = 2948807 | doi = 10.1016/j.ajhg.2010.09.010 }}
18. ^{{cite journal | vauthors = Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM | title = A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity | journal = The Journal of Biological Chemistry | volume = 285 | issue = 30 | pages = 22846–52 | date = July 2010 | pmid = 20504773 | pmc = 2906276 | doi = 10.1074/jbc.M110.122259 }}
19. ^{{cite journal | vauthors = Penno A, Reilly MM, Houlden H, Laurá M, Rentsch K, Niederkofler V, Stoeckli ET, Nicholson G, Eichler F, Brown RH, von Eckardstein A, Hornemann T | title = Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids | journal = The Journal of Biological Chemistry | volume = 285 | issue = 15 | pages = 11178–87 | date = April 2010 | pmid = 20097765 | pmc = 2856995 | doi = 10.1074/jbc.M109.092973 }}
20. ^{{cite journal | vauthors = Hornemann T, Richard S, Rütti MF, Wei Y, von Eckardstein A | title = Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase | journal = The Journal of Biological Chemistry | volume = 281 | issue = 49 | pages = 37275–81 | date = December 2006 | pmid = 17023427 | doi = 10.1074/jbc.M608066200 }}
21. ^{{cite journal | vauthors = Hornemann T, Wei Y, von Eckardstein A | title = Is the mammalian serine palmitoyltransferase a high-molecular-mass complex? | journal = The Biochemical Journal | volume = 405 | issue = 1 | pages = 157–64 | date = July 2007 | pmid = 17331073 | pmc = 1925250 | doi = 10.1042/BJ20070025 }}
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3 : EC 2.3.1|Pyridoxal phosphate enzymes|Enzymes of known structure
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