br Regulation of BCAA catabolism The BCAA

Regulation of BCAA catabolism The BCAA catabolic system is equipped in mammalian cells to dispose of excess BCAAs, presumably resulting in relatively stable concentrations of BCAAs in blood and tissues in humans. The main BCAA catabolic pathway is localized in the mitochondria of all tissues. The first 2 steps of the catabolic pathway are common to the three BCAAs (Fig. 1) [3]. The first step reaction is the transamination of BCAAs to form branched-chain α-keto acids (BCKAs), which is a reversible reaction catalyzed by branched-chain aminotransferase (BCAT). Two isozymes of BCAT have been reported; one is a mitochondrial type (BCATm or BCAT2) that is expressed in all of the peripheral tissues except for liver, and the other one is a cytosolic type (BCATc or BCAT1) that is unique to cerebral tissue, placenta, and ovaries [4]. The second step reaction is the oxidative decarboxylation of BCKAs to form CoA esters, which is catalyzed by BCKA dehydrogenase (BCKDH) complex (BCKDC). This reaction is irreversible, and it is therefore thought that BCAA catabolism is regulated by BCKDC. The activity of BCKDC is quite high in the liver of rodents compared to other organs, even though BCATm is generally not expressed in the liver [5]. BCKDC is regulated by covalent modifications: the complex is inactivated by phosphorylation of the E1 component of BCKDC and reactivated by dephosphorylation of the component. BCKDH kinase (BDK) [6,7] and BCKDH phosphatase [8,9] are responsible for these modifications, respectively. These reactions allow the rapid conversion of the activity state of BCKDC in response to alterations in the nutritional and physiological conditions of the animals. BDK is the first mitochondrial protein kinase to be cloned and its amino 13148 sequence indicates that it is more closely related to prokaryotic histidine kinases than to eukaryotic serine/threonine protein kinases [7]. The transamination of BCAAs by BCATm in the normal mammalian body under resting conditions is largely conducted in skeletal muscle, attributable to the relatively high enzyme activity in the tissue [5] and the large tissue mass (∼40% of body weight of humans) in the body. However, BCATm may mostly act at the postprandial state, because of the high Km values of BCATm (0.6–3 mM) compared to the BCAA concentrations at the postabsorptive state [10]. In contrast to BCAT, the activity of BCKDC in skeletal muscle is very low, although the affinity of BCKDC to BCKAs is very high (Km: 20–40 μM). The low activity of BCKDC in skeletal muscle is attributed to the high activity of BDK in the tissues [11] and may contribute to conserve BCAAs for protein synthesis. When BCAA supplements are ingested, plasma BCAA levels rapidly increased, peaking at ∼30 min after BCAA ingestion and thereafter gradually decreasing to normal levels in humans [2]. In this mechanism responsible for maintaining the low BCAA concentration levels, α-ketoisocaproate (a substrate of BCKDC) formed from leucine transamination acts as an inhibitor of BDK, resulting in the activation of BCKDC and then the promotion of BCAA catabolism [3].
Anabolic effects of BCAAs on protein metabolism It has been demonstrated that mammalian target of rapamycin complex 1 (mTORC1), a highly conserved serine/threonine protein kinase, regulates protein metabolism in mammals; active mTORC1 promotes protein synthesis by activating the components involved in mRNA translation and inhibits protein degradation by suppressing autophagy [12]. Although it is known that many environmental signals regulate the mTORC1 pathway, amino acids, especially leucine, are potent activators of mTORC1 [13]. It has been recently reported that sestrin2 is the leucine sensor upstream of mTORC1; the binding of leucine to sestrin2 releases mTORC1 from negative regulation [13]. Because the liver has a low capacity to metabolize BCAAs (as described above) dietary leucine can directly affect the mTORC1 pathway by increasing the plasma leucine concentration. In this context, pharmacological supplementation with BCAAs is suggested to be a promising therapeutic strategy for liver cirrhotic patients with hypoalbuminemia [14].