Serine C-palmitoyltransferase

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serine C-palmitoyltransferase
Identifiers
EC no. 2.3.1.50
CAS no. 62213-50-7
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
Serine palmitoyltransferase
SPT 2jg2.png
Crystallographic structure of serine palmitoyltransferase from S. paucimobilis . The cofactor PLP is visible in the center. [1]
Identifiers
SymbolSPT1
PDB 2JG2
UniProt Q93UV0
Other data
EC number 2.3.1.50
Search for
Structures Swiss-model
Domains InterPro
serine palmitoyltransferase, long chain base subunit 1
Identifiers
Symbol SPTLC1
Alt. symbolsHSN1
NCBI gene 10558
HGNC 11277
OMIM 605712
RefSeq NM_006415
UniProt O15269
Other data
EC number 2.3.1.50
Locus Chr. 9 q22.31
Search for
Structures Swiss-model
Domains InterPro
serine palmitoyltransferase, long chain base subunit 2
Identifiers
Symbol SPTLC2
NCBI gene 9517
HGNC 11278
OMIM 605713
RefSeq NM_004863
UniProt O15270
Other data
EC number 2.3.1.50
Locus Chr. 14 q24.3
Search for
Structures Swiss-model
Domains InterPro
serine palmitoyltransferase, long chain base subunit 3
Identifiers
SymbolSPTLC3
Alt. symbolsC20orf38, SPTLC2L
NCBI gene 55304
HGNC 16253
OMIM 611120
RefSeq NM_018327
UniProt Q9NUV7
Other data
EC number 2.3.1.50
Locus Chr. 20 p12.1
Search for
Structures Swiss-model
Domains InterPro

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

Contents

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:

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 2JG2 and 2JGT. [1]

Key active site residues of serine C-palmitoyltransferase that interact with PLP. Generated from 2JG2. Spt with plp gk.png
Key active site residues of serine C-palmitoyltransferase that interact with PLP. Generated from 2JG2.

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-keto-dihydrosphingosine is released and catalytically active PLP is reformed. 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 Sphingomonas 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 Bdellovibrio 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]

Related Research Articles

<span class="mw-page-title-main">Pyridoxal phosphate</span> Active form of vitamin B6

Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent activities, corresponding to ~4% of all classified activities. The versatility of PLP arises from its ability to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates.

<span class="mw-page-title-main">Sphingolipid</span> Family of chemical compounds

Sphingolipids are a class of lipids containing a backbone of sphingoid bases, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. These compounds play important roles in signal transduction and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with a terminal hydroxyl group is a ceramide. Other common groups bonded to the terminal oxygen atom include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.

Palmitoyl-CoA is an acyl-CoA thioester. It is an "activated" form of palmitic acid and can be transported into the mitochondrial matrix by the carnitine shuttle system, and once inside can participate in beta-oxidation. Alternatively, palmitoyl-CoA is used as a substrate in the biosynthesis of sphingosine.

<span class="mw-page-title-main">Carnitine palmitoyltransferase I</span> Enzyme found in humans

Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often palmitoylcarnitine, but other fatty acids may also be substrates. It is part of a family of enzymes called carnitine acyltransferases. This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.

Pantothenate kinase (EC 2.7.1.33, PanK; CoaA) is the first enzyme in the Coenzyme A (CoA) biosynthetic pathway. It phosphorylates pantothenate (vitamin B5) to form 4'-phosphopantothenate at the expense of a molecule of adenosine triphosphate (ATP). It is the rate-limiting step in the biosynthesis of CoA.

Palmitoyl-CoA hydrolase (EC 3.1.2.2) is an enzyme in the family of hydrolases that specifically acts on thioester bonds. It catalyzes the hydrolysis of long chain fatty acyl thioesters of acyl carrier protein or coenzyme A to form free fatty acid and the corresponding thiol:

<span class="mw-page-title-main">Carnitine O-octanoyltransferase</span>

Carnitine O-octanoyltransferase is a member of the transferase family, more specifically a carnitine acyltransferase, a type of enzyme which catalyzes the transfer of acyl groups from acyl-CoAs to carnitine, generating CoA and an acyl-carnitine. Specifically, CROT catalyzes the chemical reaction:

<span class="mw-page-title-main">SPTLC1</span> Protein-coding gene in the species Homo sapiens

Serine palmitoyltransferase, long chain base subunit 1, also known as SPTLC1, is a protein which in humans is encoded by the SPTLC1 gene.

<span class="mw-page-title-main">Phosphoglycerate dehydrogenase</span> Metabolic enzyme PHGDH

Phosphoglycerate dehydrogenase (PHGDH) is an enzyme that catalyzes the chemical reactions

<span class="mw-page-title-main">SPTLC2</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">ACOT2</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 2, also known as ACOT2, is an enzyme which in humans is encoded by the ACOT2 gene.

<span class="mw-page-title-main">ACOT4</span> Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.

<span class="mw-page-title-main">DHHC domain</span>

In molecular biology the DHHC domain is a protein domain that acts as an enzyme, which adds a palmitoyl chemical group to proteins in order to anchor them to cell membranes. The DHHC domain was discovered in 1999 and named after a conserved sequence motif found in its protein sequence. Roth and colleagues showed that the yeast Akr1p protein could palmitoylate Yck2p in vitro and inferred that the DHHC domain defined a large family of palmitoyltransferases. In mammals twenty three members of this family have been identified and their substrate specificities investigated. Some members of the family such as ZDHHC3 and ZDHHC7 enhance palmitoylation of proteins such as PSD-95, SNAP-25, GAP43, Gαs. Others such as ZDHHC9 showed specificity only toward the H-Ras protein. However, a recent study questions the involvement of classical enzyme-substrate recognition and specificity in the palmitoylation reaction. Several members of the family have been implicated in human diseases.

<span class="mw-page-title-main">ACOT6</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 6 is a protein that in humans is encoded by the ACOT6 gene. The protein, also known as C14orf42, is an enzyme with thioesterase activity.

Very-long-chain 3-oxoacyl-CoA synthase (EC 2.3.1.199, very-long-chain 3-ketoacyl-CoA synthase, very-long-chain beta-ketoacyl-CoA synthase, condensing enzyme, CUT1, CER6, FAE1, KCS, ELO) is an enzyme with systematic name malonyl-CoA:very-long-chain acyl-CoA malonyltransferase (decarboxylating and thioester-hydrolysing). This enzyme catalyses the following chemical reaction

3-hydroxydecanoyl-(acyl-carrier-protein) dehydratase (EC 4.2.1.60, D-3-hydroxydecanoyl-[acyl-carrier protein] dehydratase, 3-hydroxydecanoyl-acyl carrier protein dehydrase, 3-hydroxydecanoyl-acyl carrier protein dehydratase, β-hydroxydecanoyl thioester dehydrase, β-hydroxydecanoate dehydrase, beta-hydroxydecanoyl thiol ester dehydrase, FabA, β-hydroxyacyl-acyl carrier protein dehydratase, HDDase, β-hydroxyacyl-ACP dehydrase, (3R)-3-hydroxydecanoyl-[acyl-carrier-protein] hydro-lyase) is an enzyme with systematic name (3R)-3-hydroxydecanoyl-(acyl-carrier protein) hydro-lyase. This enzyme catalyses the following chemical reaction

Hereditary sensory and autonomic neuropathy type I or hereditary sensory neuropathy type I is a group of autosomal dominant inherited neurological diseases that affect the peripheral nervous system particularly on the sensory and autonomic functions. The hallmark of the disease is the marked loss of pain and temperature sensation in the distal parts of the lower limbs. The autonomic disturbances, if present, manifest as sweating abnormalities.

<span class="mw-page-title-main">ACOT13</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 13 is a protein that in humans is encoded by the ACOT13 gene. This gene encodes a member of the thioesterase superfamily. In humans, the protein co-localizes with microtubules and is essential for sustained cell proliferation.

<span class="mw-page-title-main">Acyl-protein thioesterase</span> Enzymes that cleave off lipid modifications on proteins

Acyl-protein thioesterases are enzymes that cleave off lipid modifications on proteins, located on the sulfur atom of cysteine residues linked via a thioester bond. Acyl-protein thioesterases are part of the α/β hydrolase superfamily of proteins and have a conserved catalytic triad. For that reason, acyl-protein thioesterases are also able to hydrolyze oxygen-linked ester bonds.

The 1-deoxysphingolipids (1-deoxySLs) are an atypical and recently discovered class of sphingolipids (SLs). They are formed during the nove synthesis pathway and their essential C1-OH deficit causes the malfunctions of the following transformations to achieve complex sphingolipids. In general, sphingolipids are formed during a reaction that is catalyzed by the SPT enzyme (serine-palmitoyltransferase) where the condensation of serine and palmitoyl-CoA takes place. The origin of this rare sphingolipid, though, is due to a defect of the SPT which can also use alanine or glycine. This change is what forms the 1-deoxySL.

References

  1. 1 2 3 Yard BA, Carter LG, Johnson KA, Overton IM, Dorward M, Liu H, McMahon SA, Oke M, Puech D, Barton GJ, Naismith JH, Campopiano DJ (July 2007). "The structure of serine palmitoyltransferase; gateway to sphingolipid biosynthesis". Journal of Molecular Biology. 370 (5): 870–86. doi:10.1016/j.jmb.2007.04.086. PMID   17559874. S2CID   7140511.
  2. 1 2 Ikushiro H, Hayashi H, Kagamiyama H (April 2003). "Bacterial serine palmitoyltransferase: a water-soluble homodimeric prototype of the eukaryotic enzyme". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1647 (1–2): 116–20. doi:10.1016/S1570-9639(03)00074-8. PMID   12686119.
  3. 1 2 3 4 Hanada K (June 2003). "Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1632 (1–3): 16–30. doi:10.1016/S1388-1981(03)00059-3. PMID   12782147.
  4. ↑ Brady RN, Di Mari SJ, Snell EE (January 1969). "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". The Journal of Biological Chemistry. 244 (2): 491–6. doi: 10.1016/S0021-9258(18)94455-8 . PMID   4388074.
  5. ↑ Stoffel W, LeKim D, Sticht G (May 1968). "Biosynthesis of dihydrosphingosine in vitro". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 349 (5): 664–70. doi:10.1515/bchm2.1968.349.1.664. PMID   4386961.
  6. ↑ Eliot AC, Kirsch JF (2004). "Pyridoxal phosphate enzymes: mechanistic, structural, and evolutionary considerations". Annual Review of Biochemistry. 73: 383–415. doi:10.1146/annurev.biochem.73.011303.074021. PMID   15189147.
  7. ↑ Han G, Gable K, Yan L, Natarajan M, Krishnamurthy J, Gupta SD, Borovitskaya A, Harmon JM, Dunn TM (December 2004). "The topology of the Lcb1p subunit of yeast serine palmitoyltransferase". The Journal of Biological Chemistry. 279 (51): 53707–16. doi: 10.1074/jbc.M410014200 . PMID   15485854.
  8. ↑ Shiraiwa Y, Ikushiro H, Hayashi H (June 2009). "Multifunctional role of His159in the catalytic reaction of serine palmitoyltransferase". The Journal of Biological Chemistry. 284 (23): 15487–95. doi: 10.1074/jbc.M808916200 . PMC   2786316 . PMID   19346561.
  9. ↑ Lowther J, Charmier G, Raman MC, Ikushiro H, Hayashi H, Campopiano DJ (June 2011). "Role of a conserved arginine residue during catalysis in serine palmitoyltransferase" (PDF). FEBS Letters. 585 (12): 1729–34. Bibcode:2011FEBSL.585.1729L. doi: 10.1016/j.febslet.2011.04.013 . PMID   21514297. S2CID   25828713.
  10. ↑ Ikushiro H, Islam MM, Okamoto A, Hoseki J, Murakawa T, Fujii S, Miyahara I, Hayashi H (October 2009). "Structural insights into the enzymatic mechanism of serine palmitoyltransferase from Sphingobacterium multivorum". Journal of Biochemistry. 146 (4): 549–62. doi:10.1093/jb/mvp100. PMID   19564159.
  11. ↑ Ikushiro H, Islam MM, Tojo H, Hayashi H (August 2007). "Molecular characterization of membrane-associated soluble serine palmitoyltransferases from Sphingobacterium multivorum and Bdellovibrio stolpii". Journal of Bacteriology. 189 (15): 5749–61. doi:10.1128/JB.00194-07. PMC   1951810 . PMID   17557831.
  12. ↑ Gable K, Slife H, Bacikova D, Monaghan E, Dunn TM (March 2000). "Tsc3p is an 80-amino acid protein associated with serine palmitoyltransferase and required for optimal enzyme activity". The Journal of Biological Chemistry. 275 (11): 7597–603. doi: 10.1074/jbc.275.11.7597 . PMID   10713067.
  13. ↑ Hanada K, Hara T, Nishijima M (March 2000). "Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques". The Journal of Biological Chemistry. 275 (12): 8409–15. doi: 10.1074/jbc.275.12.8409 . PMID   10722674.
  14. ↑ Lara PN, Moon J, Redman MW, Semrad TJ, Kelly K, Allen JW, Gitlitz BJ, Mack PC, Gandara DR (January 2015). "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 of Thoracic Oncology. 10 (1): 110–5. doi:10.1097/JTO.0000000000000385. PMC   4320001 . PMID   25490004.
  15. ↑ Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH (March 2001). "SPTLC1 is mutated in hereditary sensory neuropathy, type 1". Nature Genetics. 27 (3): 261–2. doi:10.1038/85817. PMID   11242106. S2CID   34442339.
  16. ↑ Gable K, Han G, Monaghan E, Bacikova D, Natarajan M, Williams R, Dunn TM (March 2002). "Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase". The Journal of Biological Chemistry. 277 (12): 10194–200. doi: 10.1074/jbc.M107873200 . PMID   11781309.
  17. ↑ 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 (October 2010). "Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I". American Journal of Human Genetics. 87 (4): 513–22. doi:10.1016/j.ajhg.2010.09.010. PMC   2948807 . PMID   20920666.
  18. ↑ Gable K, Gupta SD, Han G, Niranjanakumari S, Harmon JM, Dunn TM (July 2010). "A disease-causing mutation in the active site of serine palmitoyltransferase causes catalytic promiscuity". The Journal of Biological Chemistry. 285 (30): 22846–52. doi: 10.1074/jbc.M110.122259 . PMC   2906276 . PMID   20504773.
  19. ↑ 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 (April 2010). "Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids". The Journal of Biological Chemistry. 285 (15): 11178–87. doi: 10.1074/jbc.M109.092973 . PMC   2856995 . PMID   20097765.
  20. ↑ Hornemann T, Richard S, Rütti MF, Wei Y, von Eckardstein A (December 2006). "Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase". The Journal of Biological Chemistry. 281 (49): 37275–81. doi: 10.1074/jbc.M608066200 . PMID   17023427.
  21. ↑ Hornemann T, Wei Y, von Eckardstein A (July 2007). "Is the mammalian serine palmitoyltransferase a high-molecular-mass complex?". The Biochemical Journal. 405 (1): 157–64. doi:10.1042/BJ20070025. PMC   1925250 . PMID   17331073.
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