Inhibition of the PLP-dependent enzyme serine palmitoyltransferase by cycloserine: evidence for a novel decarboxylative mechanism of inactivation

Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5'-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; D-cycloserine (DCS, also known as Seromycin) is a natural product that is used to treat resistant Mycobact...

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Published inMolecular bioSystems Vol. 6; no. 9; pp. 1682 - 1693
Main Authors Lowther, Jonathan, Yard, Beverley A, Johnson, Kenneth A, Carter, Lester G, Bhat, Venugopal T, Raman, Marine C C, Clarke, David J, Ramakers, Britta, McMahon, Stephen A, Naismith, James H, Campopiano, Dominic J
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LanguageEnglish
Published England 01.01.2010
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Abstract Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5'-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; D-cycloserine (DCS, also known as Seromycin) is a natural product that is used to treat resistant Mycobacterium tuberculosis infections as well as neurological disorders since it is a potent NMDA receptor agonist, and L-cycloserine (LCS) is a synthetic enantiomer whose usefulness as a drug has been hampered by its inherent toxicity arising through inhibition of sphingolipid metabolism. Previous studies on various PLP-dependent enzymes revealed a common mechanism of inhibition by both enantiomers of CS; the PLP cofactor is disabled by forming a stable 3-hydroxyisoxazole/pyridoxamine 5'-phosphate (PMP) adduct at the active site where the cycloserine ring remains intact. Here we describe a novel mechanism of CS inactivation of the PLP-dependent enzyme serine palmitoyltransferase (SPT) from Sphingomonas paucimobilis. SPT catalyses the condensation of l-serine and palmitoyl-CoA, the first step in the de novo sphingolipid biosynthetic pathway. We have used a range of kinetic, spectroscopic and structural techniques to postulate that both LCS and DCS inactivate SPT by transamination to form a free pyridoxamine 5'-phosphate (PMP) and beta-aminooxyacetaldehyde that remain bound at the active site. We suggest this occurs by ring opening of the cycloserine ring followed by decarboxylation. Enzyme kinetics show that inhibition is reversed by incubation with excess PLP and that LCS is a more effective SPT inhibitor than DCS. UV-visible spectroscopic data, combined with site-directed mutagenesis, suggest that a mobile Arg(378) residue is involved in cycloserine inactivation of SPT.
AbstractList Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5'-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; D-cycloserine (DCS, also known as Seromycin) is a natural product that is used to treat resistant Mycobacterium tuberculosis infections as well as neurological disorders since it is a potent NMDA receptor agonist, and L-cycloserine (LCS) is a synthetic enantiomer whose usefulness as a drug has been hampered by its inherent toxicity arising through inhibition of sphingolipid metabolism. Previous studies on various PLP-dependent enzymes revealed a common mechanism of inhibition by both enantiomers of CS; the PLP cofactor is disabled by forming a stable 3-hydroxyisoxazole/pyridoxamine 5'-phosphate (PMP) adduct at the active site where the cycloserine ring remains intact. Here we describe a novel mechanism of CS inactivation of the PLP-dependent enzyme serine palmitoyltransferase (SPT) from Sphingomonas paucimobilis. SPT catalyses the condensation of l-serine and palmitoyl-CoA, the first step in the de novo sphingolipid biosynthetic pathway. We have used a range of kinetic, spectroscopic and structural techniques to postulate that both LCS and DCS inactivate SPT by transamination to form a free pyridoxamine 5'-phosphate (PMP) and beta-aminooxyacetaldehyde that remain bound at the active site. We suggest this occurs by ring opening of the cycloserine ring followed by decarboxylation. Enzyme kinetics show that inhibition is reversed by incubation with excess PLP and that LCS is a more effective SPT inhibitor than DCS. UV-visible spectroscopic data, combined with site-directed mutagenesis, suggest that a mobile Arg(378) residue is involved in cycloserine inactivation of SPT.
Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5′-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; d -cycloserine (DCS, also known as Seromycin), is a natural product that is used to treat resistant Mycobacterium tuberculosis infections as well as neurological disorders since it is a potent NMDA receptor agonist, and l -cycloserine (LCS), is a synthetic enantiomer whose usefulness as a drug has been hampered by its inherent toxicity arising through inhibition of sphingolipid metabolism. Previous studies on various PLP-dependent enzymes revealed a common mechanism of inhibition by both enantiomers of CS; the PLP cofactor is disabled by forming a stable 3-hydroxyisoxazole/pyridoxamine 5′-phosphate (PMP) adduct at the active site where the cycloserine ring remains intact. Here we describe a novel mechanism of CS inactivation of the PLP-dependent enzyme serine palmitoyltransferase (SPT) from Sphingomonas paucimobilis . SPT catalyses the condensation of l -serine and palmitoyl-CoA, the first step in the de novo sphingolipid biosynthetic pathway. We have used a range of kinetic, spectroscopic and structural techniques to postulate that both LCS and DCS inactivate SPT by transamination to form a free pyridoxamine 5′-phosphate (PMP) and β-aminooxyacetaldehyde that remain bound at the active site. We suggest this occurs by ring opening of the cycloserine ring followed by decarboxylation. Enzyme kinetics show that inhibition is reversed by incubation with excess PLP and that LCS is a more effective SPT inhibitor than DCS. UV-visible spectroscopic data, combined with site-directed mutagenesis, suggest that a mobile Arg 378 residue is involved in cycloserine inactivation of SPT.
Author Campopiano, Dominic J
Carter, Lester G
Clarke, David J
McMahon, Stephen A
Naismith, James H
Bhat, Venugopal T
Ramakers, Britta
Raman, Marine C C
Yard, Beverley A
Johnson, Kenneth A
Lowther, Jonathan
AuthorAffiliation 1 EaStChem, School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, Scotland, UK
2 Centre for Biomolecular Sciences, Scottish Structural Proteomics Facility, The University of St Andrews, Fife, KY16 9ST, Scotland, UK
AuthorAffiliation_xml – name: 1 EaStChem, School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, Scotland, UK
– name: 2 Centre for Biomolecular Sciences, Scottish Structural Proteomics Facility, The University of St Andrews, Fife, KY16 9ST, Scotland, UK
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/20445930$$D View this record in MEDLINE/PubMed
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Snippet Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5'-phosphate (PLP)-dependent enzymes....
Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5′-phosphate (PLP)-dependent enzymes....
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StartPage 1682
SubjectTerms Chromatography, Liquid
Cycloserine - chemistry
Cycloserine - pharmacology
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Mass Spectrometry
Molecular Structure
Protein Structure, Secondary
Serine C-Palmitoyltransferase - antagonists & inhibitors
Serine C-Palmitoyltransferase - chemistry
Serine C-Palmitoyltransferase - genetics
Serine C-Palmitoyltransferase - metabolism
Sphingomonas - enzymology
Title Inhibition of the PLP-dependent enzyme serine palmitoyltransferase by cycloserine: evidence for a novel decarboxylative mechanism of inactivation
URI https://www.ncbi.nlm.nih.gov/pubmed/20445930
https://pubmed.ncbi.nlm.nih.gov/PMC3670083
Volume 6
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