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Branched-Chain Amino Acids and Branched-Chain Keto Acids in Hyperammonemic States: Metabolism and As Supplements

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Branched-Chain Amino Acids and Branched-Chain Keto Acids in Hyperammonemic States: Metabolism and As Supplements H OH metabolites OH Review Branched-Chain Amino Acids and Branched-Chain Keto Acids in Hyperammonemic States: Metabolism and as Supplements Milan Holeˇcek Department of Physiology, Charles University, Faculty of Medicine in Hradec Králové, 500 03 Hradec Kralove, Czech Republic; [email protected] Received: 25 July 2020; Accepted: 7 August 2020; Published: 9 August 2020 Abstract: In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions. Keywords: glutamine; α-ketoglutarate; urea-cycle disorders; liver cirrhosis; exercise 1. Introduction Ammonia, derived mainly from the metabolism of amino acids, is toxic when present in high concentrations. Hyperammonemia due to ineffective ammonia detoxification to urea, as occurs in liver injury and urea cycle disorders (UCDs), leads to severe neurological impairments and protein-energy malnutrition development. A marked increase in blood ammonia, resulting from the activated deamination of AMP and amino acid catabolism in the muscles, promotes both central and peripheral fatigue during strenuous exercise [1–3]. Several studies have demonstrated that high levels of ammonia increase the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) [4–7], resulting in decreased BCAA levels in liver cirrhosis [8–11] and UCDs [12,13]. Due to their positive influence on protein balance and the detrimental role of decreased BCAA levels in the pathogenesis of hepatic encephalopathy, BCAAs have been recommended for patients with liver cirrhosis for almost 50 years [8]. Unfortunately, the results of clinical trials do not strongly support the theory that BCAA-containing supplements have beneficial effects [14,15]. Increased ammonia production and BCAA catabolism due to intensive Metabolites 2020, 10, 324; doi:10.3390/metabo10080324 www.mdpi.com/journal/metabolites Metabolites 2020, 10, 324x FOR PEER REVIEW 2 2of of 12 13 catabolism due to intensive exercise [16–18] were the rationale for recommending BCAA-enriched supplementsexercise [16–18 for] were athletes. the rationale Even in these for recommending cases, the benefits BCAA-enriched of BCAA-enriched supplements supplements for athletes. have Even not beenin these as great cases, as the expected benefits [19–23]. of BCAA-enriched supplements have not been as great as expected [19–23]. It has beenbeen suggestedsuggested that that the the positive positive e ffeffectsects of of BCAA BCAA mixtures mixtures are are blunted blunted by theirby their increased increased use usein the in BCAA the BCAA aminotransferase aminotransferase reaction reaction to form glutamate,to form glutamate, as a pivotal as step a pivotal in ammonia step detoxificationin ammonia detoxificationto glutamine (GLN), to glutamine in the muscles (GLN), [ 24in– the26]. muscles Adverse [24–26]. consequences Adverse include consequences the drain ofincludeα-ketoglutarate the drain (ofα -KG)α-ketoglutarate from the tricarboxylic (α-KG) from acid the (TCA) tricarboxylic cycle (cataplerosis) acid (TCA) andcycle an (cataplerosis) increased influx and of an GLN increased to the visceralinflux of tissues, GLN to where the itvisceral is catabolized tissues, into where ammonia it is catabolized (Figure1). Increased into ammonia ammonia (Figure levels 1). after Increased BCAA ammoniaadministration levels have after beenBCAA reported administration both in subjectshave been with reported liver disease both in [27 subjects–30] and with during liver physical disease [27–30]exercise and performance during physical [19–23 ].exercise performance [19–23]. Figure 1.1.Supposed Supposed effects effects of branched-chain of branched-chain amino acid am (BCAA)ino acid administration (BCAA) inadministration hyperammonemic in hyperammonemicconditions. In hyperammonemic conditions. In conditions,hyperammonemic most of theconditions, exogenous most BCAAs of the are exogenous used for the BCAAs synthesis are usedof glutamate, for the whichsynthesis is a directof glutam substrateate, which for ammonia is a direct detoxification substrate tofor glutamine ammonia (GLN). detoxification The results to glutamineare the diversion (GLN). of Theα-ketoglutarate results are (theα-KG) diversion from the of TCA α-ketoglutarate cycle (cataplerosis) (α-KG) and from GLN the catabolism TCA cycle to (cataplerosis)ammonia in the and visceral GLN tissues catabolism (particularly to ammonia the gut in and the kidneys). visceral When tissues the (p detoxificationarticularly the of ammoniagut and kidneys).to urea is compromised,When the detoxification a vicious cycle,of ammonia in which to enhancedurea is compromised, ammonia concentrations a vicious cycle, activate in which GLN enhancedsynthesis, ammonia is activated concentrat [25]. ions activate GLN synthesis, is activated [25]. For many many years, years, in in patients patients with with chronic chronic renal renal failure, failure, ammonia ammonia and andurea ureaproduction production have havebeen attenuatedbeen attenuated by the administration by the administration of ketoanalogues of ketoanalogues of essential of amino essential acids amino(KAEAAs), acids which (KAEAAs), can be whichaminated can to be the aminated original amino to the acids original [31–33]. amino Hence, acids the [ 31ability–33]. of Hence,the body the to synthesize ability of theamino body acids to fromsynthesize KAEAA amino creates acids froma theoretical KAEAA createsrationale a theoretical to use branched-chain rationale to use branched-chainketo acids (BCKAs)— keto acidsα- α α β (BCKAs)—ketoisocaproate-ketoisocaproate (KIC, ketoleucine), (KIC, ketoleucine), α-keto-β-methylvalerate-keto- -methylvalerate (KMV, (KMV,ketoisoleucine), ketoisoleucine), and andα- α ketoisovalerate-ketoisovalerate (KIV, (KIV, ketovaline)—in ketovaline)—in order order to to redu reducece ammonia ammonia production production in in liver liver cirrhosis, cirrhosis, UCDs, UCDs, and strenuous exercise. The aimaim of of this this article article is to examineis to examine the hypothesis the hy thatpothesis the adverse that the eff ectsadverse of BCAA effects administration of BCAA administrationon ammonia production on ammonia and production cataplerosis and can cataplerosis be attenuated can by be the attenuated administration by the of administration BCKAs. For this of purpose,BCKAs. For I will this assess purpose, the influence I will assess of hyperammonemia the influence of onhyperammonemia the ability of the bodyon the to ability synthesize of the BCAAs body tofrom synthesize BCKAs, alongBCAAs with from the BCKAs, results ofalong studies with examining the results the of e studiesffects of examining BCKA-enriched the effects supplements of BCKA- in enrichedliver cirrhosis, supplements UCDs, and in liver exercise. cirrhosis, UCDs, and exercise. 2. Amination of BCKAs to BCAAs under Physiological Conditions 2. Amination of BCKAs to BCAAs under Physiological Conditions The activity of BCAA aminotransferase, which enables the mutual conversion of BCAAs and The activity of BCAA aminotransferase, which enables the mutual conversion of BCAAs and BCKAs, is low in the liver and high in muscles. Therefore, most of the exogenous BCAAs (if they are BCKAs, is low in the liver and high in muscles. Therefore, most of the exogenous BCAAs (if they are not used for protein synthesis) are converted to the BCKAs in the muscles. The amino group of the not used for protein synthesis) are converted to the BCKAs in the muscles. The amino group of the BCAA is transferred to α-KG to form glutamate, which then acts as a source of an amino group to BCAA is transferred to α-KG to form glutamate, which then acts as a source of an amino group to form alanine from pyruvate or as a substrate for ammonia detoxification to GLN (Figure2—left side). form alanine from pyruvate or as a substrate for ammonia detoxification to GLN (Figure 2—left side). Metabolites 2020, 10, x FOR PEER REVIEW 3 of 12 Since the activity of BCKA dehydrogenase, which catalyzes the second and irreversible step in the oxidation of BCAAs, is low in the skeletal muscles, most of the BCKAs
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