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Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats.

Olson KC, Chen G, Xu Y, Hajnal A, Lynch CJ - Obesity (Silver Spring) (2014)

Bottom Line: This elevation was greater than that of other BCAAs (107-124%).Cytotoxic branched-chain ketoacids (BCKAs) accumulate in genetic disorders affecting BCKDC.BCKAs increase reactive oxygen species, stress kinase activation, and mitochondrial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.

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Related in: MedlinePlus

Schematic showing how impairment of BCKDC increases alloisoleucine formation. The first step in BCAA metabolism is a reversible transamination catalyzed in most peripheral tissues except liver which lacks this activity by the mitochondrial isoform of branched-chain amino acid transaminase (BCATm, BCAT2). On the left, the interconversion of L-Ile and S-ketomethylvalerate [(S)-KMV] due to BCATm activity is shown (for simplicity, the transamination partners, usually Glu and α-ketoglutarate are not shown). BCATm’s catalytic mechanism involves a covalent linkage of intermediates to the pyridoxyl-5-phosphate cofactor which in turn undergo several transitions during the reaction 20. A Schiff base aldimine of Ile first forms with the cofactor (not shown) and that in turn rearranges to an S-ketamine (shown) which is finally released as S-KMV. S-KMV can then be metabolized by BCKDC which catalyzes the next step. If BCKDC is locally inhibited, S-KMV can either enter the circulation for metabolism in another tissue such as liver or undergo reverse transamination back to Ile. Occasionally, the S-ketamine of Ile may undergo a transition to an enamine. This enamine is susceptible to tautomerization leading to an R-ketamine intermediate of Ile (shown for simplicity on the right side). The likelihood of this secondary rearrangement and tautomerization increases when KMV accumulates due to global BCKDC impairment (⊘) such as in Maple Syrup Urine Disease (MSUD). The R-ketamine can be converted to R-KMV (also a BCKDC substrate) or in a stepwise fashion to L-alloisoleucine 20 which can also exit the mitochondria and enter the circulation. Since liver lacks BCAT activity, alloisoleucine is thought to be formed in other tissues.
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Figure 1: Schematic showing how impairment of BCKDC increases alloisoleucine formation. The first step in BCAA metabolism is a reversible transamination catalyzed in most peripheral tissues except liver which lacks this activity by the mitochondrial isoform of branched-chain amino acid transaminase (BCATm, BCAT2). On the left, the interconversion of L-Ile and S-ketomethylvalerate [(S)-KMV] due to BCATm activity is shown (for simplicity, the transamination partners, usually Glu and α-ketoglutarate are not shown). BCATm’s catalytic mechanism involves a covalent linkage of intermediates to the pyridoxyl-5-phosphate cofactor which in turn undergo several transitions during the reaction 20. A Schiff base aldimine of Ile first forms with the cofactor (not shown) and that in turn rearranges to an S-ketamine (shown) which is finally released as S-KMV. S-KMV can then be metabolized by BCKDC which catalyzes the next step. If BCKDC is locally inhibited, S-KMV can either enter the circulation for metabolism in another tissue such as liver or undergo reverse transamination back to Ile. Occasionally, the S-ketamine of Ile may undergo a transition to an enamine. This enamine is susceptible to tautomerization leading to an R-ketamine intermediate of Ile (shown for simplicity on the right side). The likelihood of this secondary rearrangement and tautomerization increases when KMV accumulates due to global BCKDC impairment (⊘) such as in Maple Syrup Urine Disease (MSUD). The R-ketamine can be converted to R-KMV (also a BCKDC substrate) or in a stepwise fashion to L-alloisoleucine 20 which can also exit the mitochondria and enter the circulation. Since liver lacks BCAT activity, alloisoleucine is thought to be formed in other tissues.

Mentions: BCAAs, Phe and alloisoleucine were measured in plasma by UPLC-MS. Compared to lean rats, obesity elevated BCAAs by 107–124% on average in plasma from obese Zucker rats (lean vs obese: Ile, 42 ± 3 vs 87 ± 3 μM; Leu, 85 ± 5 vs 190 ± 10 μM; Val, 125 ± 7 vs 266 ± 9 μM; n=9/group, p<0.001). Phenylalanine was elevated 24% (67 ± 1 vs 83 ± 2 μM, p<0.001). Alloisoleucine is the R-epimer of Ile, formed as a rare side reaction during the reversible transamination of Ile or S-ketomethlyvalerate (S-KMV) 20. The mechanism of its formation is schematically shown in Fig 1. In obese Zucker rats, alloisoleucine was elevated 238% (Fig 2A), with some individual values between 1.3 and 1.8 μM (not shown). No significant correlation was observed between plasma Ile and alloisoleucine concentrations in either lean or obese rats (data not shown).


Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats.

Olson KC, Chen G, Xu Y, Hajnal A, Lynch CJ - Obesity (Silver Spring) (2014)

Schematic showing how impairment of BCKDC increases alloisoleucine formation. The first step in BCAA metabolism is a reversible transamination catalyzed in most peripheral tissues except liver which lacks this activity by the mitochondrial isoform of branched-chain amino acid transaminase (BCATm, BCAT2). On the left, the interconversion of L-Ile and S-ketomethylvalerate [(S)-KMV] due to BCATm activity is shown (for simplicity, the transamination partners, usually Glu and α-ketoglutarate are not shown). BCATm’s catalytic mechanism involves a covalent linkage of intermediates to the pyridoxyl-5-phosphate cofactor which in turn undergo several transitions during the reaction 20. A Schiff base aldimine of Ile first forms with the cofactor (not shown) and that in turn rearranges to an S-ketamine (shown) which is finally released as S-KMV. S-KMV can then be metabolized by BCKDC which catalyzes the next step. If BCKDC is locally inhibited, S-KMV can either enter the circulation for metabolism in another tissue such as liver or undergo reverse transamination back to Ile. Occasionally, the S-ketamine of Ile may undergo a transition to an enamine. This enamine is susceptible to tautomerization leading to an R-ketamine intermediate of Ile (shown for simplicity on the right side). The likelihood of this secondary rearrangement and tautomerization increases when KMV accumulates due to global BCKDC impairment (⊘) such as in Maple Syrup Urine Disease (MSUD). The R-ketamine can be converted to R-KMV (also a BCKDC substrate) or in a stepwise fashion to L-alloisoleucine 20 which can also exit the mitochondria and enter the circulation. Since liver lacks BCAT activity, alloisoleucine is thought to be formed in other tissues.
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Related In: Results  -  Collection

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Figure 1: Schematic showing how impairment of BCKDC increases alloisoleucine formation. The first step in BCAA metabolism is a reversible transamination catalyzed in most peripheral tissues except liver which lacks this activity by the mitochondrial isoform of branched-chain amino acid transaminase (BCATm, BCAT2). On the left, the interconversion of L-Ile and S-ketomethylvalerate [(S)-KMV] due to BCATm activity is shown (for simplicity, the transamination partners, usually Glu and α-ketoglutarate are not shown). BCATm’s catalytic mechanism involves a covalent linkage of intermediates to the pyridoxyl-5-phosphate cofactor which in turn undergo several transitions during the reaction 20. A Schiff base aldimine of Ile first forms with the cofactor (not shown) and that in turn rearranges to an S-ketamine (shown) which is finally released as S-KMV. S-KMV can then be metabolized by BCKDC which catalyzes the next step. If BCKDC is locally inhibited, S-KMV can either enter the circulation for metabolism in another tissue such as liver or undergo reverse transamination back to Ile. Occasionally, the S-ketamine of Ile may undergo a transition to an enamine. This enamine is susceptible to tautomerization leading to an R-ketamine intermediate of Ile (shown for simplicity on the right side). The likelihood of this secondary rearrangement and tautomerization increases when KMV accumulates due to global BCKDC impairment (⊘) such as in Maple Syrup Urine Disease (MSUD). The R-ketamine can be converted to R-KMV (also a BCKDC substrate) or in a stepwise fashion to L-alloisoleucine 20 which can also exit the mitochondria and enter the circulation. Since liver lacks BCAT activity, alloisoleucine is thought to be formed in other tissues.
Mentions: BCAAs, Phe and alloisoleucine were measured in plasma by UPLC-MS. Compared to lean rats, obesity elevated BCAAs by 107–124% on average in plasma from obese Zucker rats (lean vs obese: Ile, 42 ± 3 vs 87 ± 3 μM; Leu, 85 ± 5 vs 190 ± 10 μM; Val, 125 ± 7 vs 266 ± 9 μM; n=9/group, p<0.001). Phenylalanine was elevated 24% (67 ± 1 vs 83 ± 2 μM, p<0.001). Alloisoleucine is the R-epimer of Ile, formed as a rare side reaction during the reversible transamination of Ile or S-ketomethlyvalerate (S-KMV) 20. The mechanism of its formation is schematically shown in Fig 1. In obese Zucker rats, alloisoleucine was elevated 238% (Fig 2A), with some individual values between 1.3 and 1.8 μM (not shown). No significant correlation was observed between plasma Ile and alloisoleucine concentrations in either lean or obese rats (data not shown).

Bottom Line: This elevation was greater than that of other BCAAs (107-124%).Cytotoxic branched-chain ketoacids (BCKAs) accumulate in genetic disorders affecting BCKDC.BCKAs increase reactive oxygen species, stress kinase activation, and mitochondrial dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.

Show MeSH
Related in: MedlinePlus