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Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents

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Abstract

Cysteine S-conjugate β-lyases are pyridoxal 5′-phosphate-containing enzymes that catalyze β-elimination reactions with cysteine S-conjugates that possess a good leaving group in the β-position. The end products are aminoacrylate and a sulfur-containing fragment. The aminoacrylate tautomerizes and hydrolyzes to pyruvate and ammonia. The mammalian cysteine S-conjugate β-lyases thus far identified are enzymes involved in amino acid metabolism that catalyze β-lyase reactions as non-physiological side reactions. Most are aminotransferases. In some cases the lyase is inactivated by reaction products. The cysteine S-conjugate β-lyases are of much interest to toxicologists because they play an important key role in the bioactivation (toxication) of halogenated alkenes, some of which are produced on an industrial scale and are environmental contaminants. The cysteine S-conjugate β-lyases have been reviewed in this journal previously (Cooper and Pinto in Amino Acids 30:1–15, 2006). Here, we focus on more recent findings regarding: (1) the identification of enzymes associated with high-M r cysteine S-conjugate β-lyases in the cytosolic and mitochondrial fractions of rat liver and kidney; (2) the mechanism of syncatalytic inactivation of rat liver mitochondrial aspartate aminotransferase by the nephrotoxic β-lyase substrate S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (the cysteine S-conjugate of tetrafluoroethylene); (3) toxicant channeling of reactive fragments from the active site of mitochondrial aspartate aminotransferase to susceptible proteins in the mitochondria; (4) the involvement of cysteine S-conjugate β-lyases in the metabolism/bioactivation of drugs and natural products; and (5) the role of cysteine S-conjugate β-lyases in the metabolism of selenocysteine Se-conjugates. This review emphasizes the fact that the cysteine S-conjugate β-lyases are biologically more important than hitherto appreciated.

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Abbreviations

AlaAT:

Alanine aminotransferase

AGAT II:

Alanine-glyoxylate aminotransferase isoenzyme II

BCATc :

Cytosolic branched-chain aminotransferase

BCATm :

Mitochondrial branched-chain aminotransferase

BCDHC:

Branched-chain α-keto acid dehydrogenase complex

BTC:

S-(2-Benzothiazolyl)-l-cysteine

cAAT:

Cytosolic aspartate aminotransferase

DCVC:

S-(1,2-Dichlorovinyl)-l-cysteine

DFTAL:

Difluorothioamidyl-lysine

EDAG:

γ-Glutamyldehydroalanylglycine

ESI-MS:

Electrospray ionization-mass spectrometry

GSH:

Glutathione

GST:

Glutathione S-transferase

GTK:

Glutamine transaminase K

HSP60:

Heat shock protein 60 kDa

HSP70i :

Heat shock protein 70 kDa (inducible isoform)

Hsc70:

Cytosolic HSP70

KAT I:

Kynurenine aminotransferase isoenzyme I

KGDHC:

α-Ketoglutarate dehydrogenase complex

mAAT:

Mitochondrial aspartate aminotransferase

mitACON:

Mitochondrial aconitase

mitHSP70:

Heat shock protein 70 kDa (mitochondrial isoform)

mitGTK:

Mitochondrial GTK

pmAAT:

Precursor to mAAT

PDHC:

Pyruvate dehydrogenase complex

PLP:

Pyridoxal 5′-phosphate

PMP:

Pyridoxamine 5′-phosphate

SAC:

S-Allyl-l-cysteine

SAMC:

S-Allylmercapto-l-cysteine

TCA cycle:

Tricarboxylic acid cycle

TFA:

Trifluoroacetic acid

TFEC:

S-(1,1,2,2-Tetrafluoroethyl)-l-cysteine

THT:

Tetrahydrothiophene

THT-A:

β-(S-Tetrahydrothiophenium)-l-alanine

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Acknowledgments

Part of the work cited from the authors’ laboratories was supported by NIH grants RO1 ES8421 (AJLC), CA111842 (JTP), GM51916 (SAB) National Institute of Justice Grant IJ-CX-K014 (PSC),University of Kansas Medical Center ROV10525 (AA).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, USA

    Arthur J. L. Cooper, Boris F. Krasnikov & John T. Pinto

  2. Columbia University, New York, NY, USA

    Zoya V. Niatsetskaya

  3. Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA

    Patrick S. Callery

  4. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA

    Maria T. Villar & Antonio Artigues

  5. Laural Consulting, Adelaide, Australia

    Sam A. Bruschi

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  1. Arthur J. L. Cooper
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Correspondence to Arthur J. L. Cooper.

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Cooper, A.J.L., Krasnikov, B.F., Niatsetskaya, Z.V. et al. Cysteine S-conjugate β-lyases: important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents. Amino Acids 41, 7–27 (2011). https://doi.org/10.1007/s00726-010-0552-0

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