While fatty acids are essential components of membrane structure and energy storage, their functions in cellular signaling, protein activation, and regulation of inflammatory, immune and other stress responses are equally important. The long-range goal of this project is to more broadly characterize the metabolism of acyl- CoAs and to identify the consequences of its failure in humans. Specifically, this renewal application will further examine the metabolism of branched chain and other unusual fatty acids. In humans, the acyl-CoA dehydrogenase (ACD) family consists of 11 evolutionarily conserved flavoenzymes involved in either branched chain amino acid metabolism or fatty acid 2-oxidation. Genetic deficiencies that cause significant morbidity and mortality have been identified in nine of the ACDs. We identified two new ACDs (ACD10 and 11) that are the most evolutionarily conserved members of this family. They have a more complicated gene structure and more limited tissue distribution than the other ACDs. They also appear to use less abundant, unusual substrates. This renewal application has three specific aims.
Specific Aim 1 is to characterize the role of ACD10 and 11 in human metabolism a.
Specific aim 1 a is to characterize the enzymatic properties of the two major products of the ACD10 and 11 loci. In contrast to other ACDs, the ACD10 and 11 genes include an extra APH domain at the N-terminus. I hypothesize that in humans these genes will support expression of at least two major proteins, one containing both domains and another consisting of just the ACD domain, that will differ in their subcellular localization. I predict that the ACD10 and 11 proteins containing only the ACD domain will be located in mitochondrial.
Specific aim 1 b is to characterize the substrate specificity of the two primary products of ACD10 and 11. I hypothesize that full length ACD11 degrades aromatic butyrate derivatives in peroxisomes, while the shorter form oxidizes isobranched chain and straight chain acyl-CoA substrates with 1- carbon backbones of more than 18 carbons in mitochondria.
Specific Aim 2 is to characterize an ACD11 deficient mouse.
Specific Aim 2 a is to characterize the biochemical phenotype of the ACD11 deficient mouse.
Specific Aim 2 b is to characterize the clinical phenotype of the ADC11 deficient mouse.
Specific Aim 3 is to identify and characterize patients with deficiencies in degrading branched chain acyl-CoAs.
Specific Aim 3 a is to identify patients with a deficiency of ACD10 and 11.
Specific Aim 3 b is to expand the characterization of SBCAD and IBD deficiency to understand their clinical and mutation spectrums.

Public Health Relevance

Fatty acids are important chemicals that are used to generate fuel for the body. We have discovered two new proteins that use fatty acids for other important body processes. We have also identified a possible new genetic disorder caused by a deficiency of these proteins. Understanding the functions of these proteins will give us better tools to diagnose and treat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054936-12
Application #
8418708
Study Section
Special Emphasis Panel (ZRG1-TAG-M (01))
Program Officer
Mckeon, Catherine T
Project Start
1999-02-15
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
12
Fiscal Year
2013
Total Cost
$264,939
Indirect Cost
$86,527
Name
University of Pittsburgh
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Luis, Paula B M; Ruiter, Jos P N; Ijlst, Lodewijk et al. (2011) Role of isovaleryl-CoA dehydrogenase and short branched-chain acyl-CoA dehydrogenase in the metabolism of valproic acid: implications for the branched-chain amino acid oxidation pathway. Drug Metab Dispos 39:1155-60

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