Branched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of multiple enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). Three different acyl-CoA dehydrogenases (ACADs) are active in each catabolic pathway and genetic deficiencies in each have been identified. While characteristic metabolites related to the enzymatic block accumulate in each deficiency, for reasons that are not clear, clinical symptoms are only seen in the context of deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the leucine pathway. Metabolism of fibroblasts derived from patients with mutations in each of the BCAA ACADs were characterized using metabolomics to better understand the flux of BCAA through their respective pathways. Stable isotope labeled LEU, ILE, and VAL in patient and control cell lines revealed that mutations in isobutyryl-CoA dehydrogenase (IBDH in the valine pathway) lead to a significant increase in isobutyrylcarnitine (a surrogate for the enzyme substrate isobutyryl-CoA) leading to metabolism by short-branched chain acyl-CoA dehydrogenase (SBCADH in the isoleucine pathway) and production of the pathway end product propionylcarnitine (a surrogate for propionyl-CoA). Similar cross activity was observed for SBCADH deficient patient cells, leading to a significant increase in propionylcarnitine, presumably by metabolism of 2 methylbutyryl-CoA via IBDH activity. Labeled BCAA studies identified that the majority of the intracellular propionyl-CoA pool in fibroblasts is generated from isoleucine, but heptanoic acid (a surrogate for odd-chain fatty acids) is also efficiently converted to propionate.

中文翻译：

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代谢分析揭示了支链氨基酸分解代谢串扰的证据，以及改善有机酸尿症治疗的潜力。

支链氨基酸（BCAA）代谢发生在线粒体基质中，并且由多种酶组成，一些酶共有，并被组织成三个途径来分解亮氨酸，异亮氨酸和缬氨酸（分别为LEU，ILE和VAL）。三种不同的酰基辅酶A脱氢酶（ACAD）在每种分解代谢途径中均具有活性，并且已鉴定出每种遗传缺陷。尽管与酶促阻滞有关的特征性代谢产物会在每种缺陷中积累，但由于不清楚的原因，仅在亮氨酸途径中异戊酰-CoA脱氢酶（IVDH）缺乏的情况下才能看到临床症状。使用代谢组学对源自每个BCAA ACAD中具有突变的患者的成纤维细胞的代谢进行表征，以更好地了解BCAA通过其各自途径的通量。患者和对照细胞系中标记有LEU，ILE和VAL的​​稳定同位素显示，异丁酰-CoA脱氢酶（缬氨酸途径中的IBDH）突变导致异丁酰肉碱（酶底物异丁酰-CoA的替代物）显着增加，从而导致通过短支链酰基辅酶A脱氢酶（异亮氨酸途径中的SBCADH）进行代谢和途径终产物丙酰肉碱（丙酰辅酶A的替代物）的产生。对于SBCADH缺陷的患者细胞，观察到相似的交叉活性，导致丙酰肉碱显着增加，大概是通过IBDH活性代谢了2个甲基丁酰-CoA。标记的BCAA研究表明，成纤维细胞中的大部分细胞内丙酰辅酶A池是由异亮氨酸产生的，