The Pyridoxal 5′-Phosphate (PLP)-Dependent Enzyme Serine Palmitoyltransferase (SPT): Effects of the Small Subunits and Insights from Bacterial Mimics of Human hLCB2a HSAN1 Mutations
Joint Authors
Campopiano, Dominic
Beattie, Ashley E.
Gupta, Sita D.
Frankova, Lenka
Kazlauskaite, Agne
Harmon, Jeffrey M.
Dunn, Teresa M.
Source
Issue
Vol. 2013, Issue 2013 (31 Dec. 2013), pp.1-13, 13 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2013-09-22
Country of Publication
Egypt
No. of Pages
13
Main Subjects
Abstract EN
The pyridoxal 5′-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) catalyses the first step of de novo sphingolipid biosynthesis.
The core human enzyme is a membrane-bound heterodimer composed of two subunits (hLCB1 and hLCB2a/b), and mutations in both hLCB1 (e.g., C133W and C133Y) and hLCB2a (e.g., V359M, G382V, and I504F) have been identified in patients with hereditary sensory and autonomic neuropathy type I (HSAN1), an inherited disorder that affects sensory and autonomic neurons.
These mutations result in substrate promiscuity, leading to formation of neurotoxic deoxysphingolipids found in affected individuals.
Here we measure the activities of the hLCB2a mutants in the presence of ssSPTa and ssSPTb and find that all decrease enzyme activity.
High resolution structural data of the homodimeric SPT enzyme from the bacterium Sphingomonas paucimobilis (Sp SPT) provides a model to understand the impact of the hLCB2a mutations on the mechanism of SPT.
The three human hLCB2a HSAN1 mutations map onto Sp SPT (V246M, G268V, and G385F), and these mutant mimics reveal that the amino acid changes have varying impacts; they perturb the PLP cofactor binding, reduce the affinity for both substrates, decrease the enzyme activity, and, in the most severe case, cause the protein to be expressed in an insoluble form.
American Psychological Association (APA)
Beattie, Ashley E.& Gupta, Sita D.& Frankova, Lenka& Kazlauskaite, Agne& Harmon, Jeffrey M.& Dunn, Teresa M.…[et al.]. 2013. The Pyridoxal 5′-Phosphate (PLP)-Dependent Enzyme Serine Palmitoyltransferase (SPT): Effects of the Small Subunits and Insights from Bacterial Mimics of Human hLCB2a HSAN1 Mutations. BioMed Research International،Vol. 2013, no. 2013, pp.1-13.
https://search.emarefa.net/detail/BIM-1003672
Modern Language Association (MLA)
Beattie, Ashley E.…[et al.]. The Pyridoxal 5′-Phosphate (PLP)-Dependent Enzyme Serine Palmitoyltransferase (SPT): Effects of the Small Subunits and Insights from Bacterial Mimics of Human hLCB2a HSAN1 Mutations. BioMed Research International No. 2013 (2013), pp.1-13.
https://search.emarefa.net/detail/BIM-1003672
American Medical Association (AMA)
Beattie, Ashley E.& Gupta, Sita D.& Frankova, Lenka& Kazlauskaite, Agne& Harmon, Jeffrey M.& Dunn, Teresa M.…[et al.]. The Pyridoxal 5′-Phosphate (PLP)-Dependent Enzyme Serine Palmitoyltransferase (SPT): Effects of the Small Subunits and Insights from Bacterial Mimics of Human hLCB2a HSAN1 Mutations. BioMed Research International. 2013. Vol. 2013, no. 2013, pp.1-13.
https://search.emarefa.net/detail/BIM-1003672
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1003672