A structural mapping of mutations causing succinyl‐CoA:3‐ketoacid CoA transferase (SCOT) deficiency

Naeem Shafqat,Wyatt W Yue,Ernst Christensen,Toshiyuki Fukao,Udo Oppermann,Kate L Kavanagh,Jörn Oliver Sass,Wen Hwa Lee

doi:10.1007/s10545-013-9589-z

Abstract

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inherited metabolic disorder of ketone metabolism, characterized by ketoacidotic episodes and often permanent ketosis. To date there are ∼20 disease-associated alleles on the OXCT1 gene that encodes the mitochondrial enzyme SCOT. SCOT catalyzes the first, rate-limiting step of ketone body utilization in peripheral tissues, by transferring a CoA moiety from succinyl-CoA to form acetoacetyl-CoA, for entry into the tricarboxylic acid cycle for energy production. We have determined the crystal structure of human SCOT, providing a molecular understanding of the reported mutations based on their potential structural effects. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the web address: http://www.thesgc.org/jimd/SCOT.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-013-9589-z) contains supplementary material, which is available to authorized users.

Highlights

Ketone bodies, predominantly produced in the liver, provide extrahepatic organs such as heart and brain with energy when glucose supply is limited (Sass 2012)
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users
SuccinylCoA:3-ketoacid CoA transferase (SCOT) is a mitochondrial enzyme expressed in all extrahepatic tissues, but abundant in the heart, brain and kidney (Fukao et al 1997)

Summary

Introduction

Ketone bodies (acetoacetate, 3-hydroxybutyrate, acetone), predominantly produced in the liver, provide extrahepatic organs such as heart and brain with energy when glucose supply is limited (Sass 2012). SuccinylCoA:3-ketoacid CoA transferase (SCOT; gene name OXCT1; EC 2.8.3.5) catalyzes the first and rate-determining. T. Fukao Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan. T. Fukao Medical information Sciences Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1194, Japan. SCOT is a mitochondrial enzyme expressed in all extrahepatic tissues, but abundant in the heart, brain and kidney (Fukao et al 1997). Mutations in the human OXCT1 gene on chromosome location 5p13 result in the rare autosomal recessive deficiency of SCOT (OMIM 245050) (Mitchell and Fukao 2001). We report the crystal structure of human SCOT, and present an interactive mapping of missense mutations to understand the molecular basis of SCOT deficiency

14 Leu429

Experimental procedures

Results and discussion