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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-TAG-M (01))
Program Officer
Mckeon, Catherine T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Bloom, Kaitlyn; Mohsen, Al-Walid; Karunanidhi, Anuradha et al. (2018) Investigating the link of ACAD10 deficiency to type 2 diabetes mellitus. J Inherit Metab Dis 41:49-57
Mohsen, Al-Walid A; Vockley, Jerry (2015) Kinetic and spectral properties of isovaleryl-CoA dehydrogenase and interaction with ligands. Biochimie 108:108-19
Wang, Wei; Mohsen, Al-Walid; Uechi, Guy et al. (2014) Complex changes in the liver mitochondrial proteome of short chain acyl-CoA dehydrogenase deficient mice. Mol Genet Metab 112:30-9
Van Calcar, Sandra C; Baker, Mei W; Williams, Phillip et al. (2013) Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin. Mol Genet Metab 110:111-5
Pan, Lisa; Vockley, Jerry (2013) Neuropsychiatric Symptoms in Inborn Errors of Metabolism: Incorporation of Genomic and Metabolomic Analysis into Therapeutics and Prevention. Curr Genet Med Rep 1:65-70
Waisbren, Susan E; Landau, Yuval; Wilson, Jenna et al. (2013) Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev 17:260-8
Knerr, Ina; Weinhold, Natalie; Vockley, Jerry et al. (2012) Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J Inherit Metab Dis 35:29-40
Kormanik, Kaitlyn; Kang, Heejung; Cuebas, Dean et al. (2012) Evidence for involvement of medium chain acyl-CoA dehydrogenase in the metabolism of phenylbutyrate. Mol Genet Metab 107:684-9
Michaliszyn, Sara F; Sjaarda, Lindsey A; Mihalik, Stephanie J et al. (2012) Metabolomic profiling of amino acids and ?-cell function relative to insulin sensitivity in youth. J Clin Endocrinol Metab 97:E2119-24
Schiff, Manuel; BĂ©nit, Paule; Jacobs, Howard T et al. (2012) Therapies in inborn errors of oxidative metabolism. Trends Endocrinol Metab 23:488-95

Showing the most recent 10 out of 36 publications