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HMB is synthesized in the human body through the metabolism of leucine|, a branched-chain amino acid. 
The vast majority of  metabolism is initially catalyzed by the branched-chain amino acid aminotransferase enzyme, producing  (α-KIC). α-KIC is mostly metabolized by the mitochondrial enzyme branched-chain  dehydrogenase, which converts it to isovaleryl-CoA. Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to , which is used in the synthesis of acetyl-CoA and other compounds. During biotin deficiency, HMB can be synthesized from  via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert  into  and  into HMB respectively. A relatively small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase (KIC dioxygenase), which converts α-KIC to HMB. In healthy individuals, this minor pathway – which involves the conversion of  to α-KIC and then HMB – is the predominant route of HMB synthesis.