Wilcken, Rainer and Srinivas, Honnappa (2016) Mutational analysis of SGPL1: In silico modelling (The analysis results will be shared with Prof. Friedhelm Hildebrandt, Harvard medical school, Division of Nephrology Boston Children's Hospital). These results ( were approved in OAK before), that were shared with Prof. Friedhelm Hildebrandt is now a part of full manuscript for publication with Prof. Friedhelm Hildebrandt as corresponding author . Honnappa Srinivas and Rainer Wilken are the co-authors from NIBR. Please find attached the full manuscript. SGPL1 mutations cause nephrosis with ichthyosis and adrenal insufficiency.

Abstract

Sphingosine-1-phosphate lyase (SGPL1), a key enzyme of sphingolipid metabolism, catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. . Its main substrate sphingosine-1-phosphate (S1P) acts both extracellularly, by binding G protein-coupled receptors of the lysophospholipid receptor family, and inside the cell, as a second messenger. Therefore, S1P takes part in regulating various cellular processes and its levels are tightly regulated.

SGPL1 is a symmetric homodimer; two subunits form a tightly intertwined dimer with both chains contributing to the catalytic cavity defined by the covalently bound cofactor pyridoxal phosphate (PLP). Two mutations (R222Q and S346Ile) were found in individuals from families with nephrotic syndrome (unpublished data, Prof. Friedhelm Hildebrandt, Harvard medical school, Division of Nephrology Boston Children's Hospital). To understand the structural changes due to these mutations, we have performed an in silico modelling analysis. The published SGPL1 structure (PDB accession 4Q6R) served as a basis for our in silico model analysis to derive qualitative measure of protein stability and dimer affinity.

Item Type:	Article
Keywords:	SGPL1, Mutations, crystal structure, Modelling
Date Deposited:	30 Jun 2016 23:45
Last Modified:	30 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25460