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Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism
C R Roe1, S D Cederbaum, D S Roe
1Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas. cr.roe@baylordallas.edu
Insights
This study identifies a distinct isobutyryl-CoA dehydrogenase enzyme in humans, crucial for valine metabolism. This finding differentiates human metabolic pathways from those in rats, impacting our understanding of genetic disorders.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Carnitine deficiency and dilated cardiomyopathy in a pediatric patient suggested a metabolic anomaly.
- Initial investigations ruled out common fatty acid oxidation defects like SCAD deficiency.
Observation:
- Isotope tracing in patient fibroblasts showed normal metabolism of palmitate and leucine but abnormal valine breakdown.
- Specifically, 13C5-valine led to increased 13C4-isobutyrylcarnitine, indicating a block in valine catabolism.
- This pattern differed from ETF-QO deficiency, highlighting a unique enzymatic defect.
Findings:
- The patient's fibroblasts exhibited a deficiency in isobutyryl-CoA dehydrogenase, a distinct enzyme solely involved in human valine metabolism.
- This contrasts with rats, where a single 2-methyl branched-chain dehydrogenase handles both valine and isoleucine pathways.
Implications:
- Establishes the existence of a separate isobutyryl-CoA dehydrogenase in humans, crucial for valine catabolism.
- Provides a basis for diagnosing novel inborn errors of metabolism affecting valine processing.
- Enhances understanding of species-specific metabolic pathway divergence.
Abstract:
A 2-year-old female was well until 12 months of age when she was found to be anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 microM and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In vitro analysis of the mitochondrial pathways for beta oxidation, and leucine, valine, and isoleucine metabolism was performed in fibroblasts using stable isotope-labeled precursors to these pathways followed by acylcarnitine analysis by tandem mass spectrometry. 16-2H3-palmitate was metabolized normally down to the level of butyryl-CoA thus excluding SCAD deficiency. 13C6-leucine and 13C6-isoleucine were also metabolized normally. 13C5-valine incubation revealed a significant increase in 13C4-isobutyrylcarnitine without any incorporation into propionylcarnitine as is observed normally. These same precursors were also evaluated in fibroblasts with proven ETF-QO deficiency in which acyl-CoA dehydrogenase deficiencies in each of these pathways was clearly identified. These results indicate that in the human, there is an isobutyryl-CoA dehydrogenase which exists as a separate enzyme serving only the valine pathway in addition to the 2-methyl branched-chain dehydrogenase which serves both the valine and the isoleucine pathways in both rat and human.