The role of glutamine transaminase K (GTK) in sulfur and α-keto acid metabolism in the brain, and in the possible bioactivation of neurotoxicants

被引:97
作者
Cooper, AJL
机构
[1] Cornell Univ, Weill Med Coll, Burke Med Res Inst, Dept Biochem, White Plains, NY 10605 USA
[2] Cornell Univ, Weill Med Coll, Burke Med Res Inst, Dept Neurol & Neurosci, White Plains, NY 10605 USA
关键词
glutamine transaminase K; sulfur metabolism; alpha-keto acid metabolism; kynurenine aminotransferase; bioactivation of neurotoxicants;
D O I
10.1016/j.neuint.2003.12.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glutamine transaminase K (GTK), which is a freely reversible glutamine (methionine) aromatic amino acid aminotransferase, is present in most mammalian tissues, including brain. Quantitatively, the most important amine donor in vivo is glutamine. The product of glutamine transamination (i.e., alpha-ketoglutaramate; alphaKGM) is rapidly removed by cyclization and/or conversion to alpha-ketoglutarate. Transamination is therefore "pulled" in the direction of glutamine utilization. Major biological roles of GTK are to maintain low levels of phenylpyruvate and to close the methionine salvage pathway. GTK also catalyzes the transamination of cystathionine, lanthionine, and thialysine to the corresponding alpha-keto acids, which cyclize to ketimines. The cyclic ketimines and several metabolites derived there from are found in brain. It is not clear whether these compounds have a biological function or are metabolic dead-ends. However, high-affinity binding of lanthionine ketimine (LK) to brain membranes has been reported. Mammalian tissues possess several enzymes capable of catalyzing transamination of kynurenine in vitro. Two of these kynurenine aminotransferases (KATs), namely KAT I and KAT II, are present in brain and have been extensively studied. KAT I and KAT II are identical to GTK and alpha-aminoadipate aminotransferase, respectively. GTK/KAT I is largely cytosolic in kidney, but mostly mitochondrial in brain. The same gene codes for both forms, but alternative splicing dictates whether a 32-amino acid mitochondrial-targeting sequence is present in the expressed protein. The activity of KAT I is altered by a missense mutation (E61G) in the spontaneously hypertensive rat. The symptoms may be due in part to alteration of kynurenine transamination. However, owing to strong competition from other amino acid substrates, the turnover of kynurenine to kynurenate by GTK/KAT I in nervous tissue must be slow unless kynurenine and GTK are sequestered in a compartment distinct from the major amino acid pools. The possibility is discussed that the spontaneous hypertension in rats carrying the GTK/KAT I mutation may be due in part to disruption of glutamine transamination. GTK is one of several pyridoxal 5'-phosphate (PLP)-containing enzymes that can catalyze non-physiological beta-elimination reactions with cysteine S-conjugates containing a good leaving group attached at the sulfur. These elimination reactions may contribute to the bioactivation of certain electrophiles, resulting in toxicity to kidney, liver, brain, and possibly other organs. On the other hand, the beta-lyase reaction catalyzed by GTK may be useful in the conversion of some cysteine S-conjugate prodrugs to active components in vivo. The roles of GTK in (a) brain nitrogen, sulfur, and aromatic amino acid/kynurenine metabolism, (b) brain alpha-keto acid metabolism, (c) bioactivation of certain electrophiles in brain, (d) prodrug targeting, and (e) maintenance of normal blood pressure deserve further study. (C) 2004 Elsevier Ltd. All rights reserved.
引用
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页码:557 / 577
页数:21
相关论文
共 187 条
[1]   REGIONAL PATTERN AND HEAT-RESISTANCE OF BRAIN 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE [J].
ABBRUZZESE, A ;
DELLAPIETRA, G ;
PORTA, R .
EXPERIENTIA, 1986, 42 (07) :820-821
[2]   OCCURRENCE OF 5'-DEOXY-5'-METHYLTHIOADENOSINE PHOSPHORYLASE IN THE MAMMALIAN CNS - DISTRIBUTION AND KINETIC-STUDIES ON THE RAT-BRAIN ENZYME [J].
ABBRUZZESE, A ;
DELLAPIETRA, G ;
PORTA, R .
JOURNAL OF NEUROCHEMISTRY, 1983, 40 (02) :487-492
[3]   GLUTAMINE TRANSAMINASE-K AND CYSTEINE-S-CONJUGATE BETA-LYASE ACTIVITY STAINS [J].
ABRAHAM, DG ;
COOPER, AJL .
ANALYTICAL BIOCHEMISTRY, 1991, 197 (02) :421-427
[4]   Cloning and expression of a rat kidney cytosolic glutamine transaminase K that has strong sequence homology to kynurenine pyruvate aminotransferase [J].
Abraham, DG ;
Cooper, AJL .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1996, 335 (02) :311-320
[5]  
ALBERATIGIANI D, 1995, J NEUROCHEM, V64, P1448
[6]   Glutathione-dependent bioactivation of haloalkenes [J].
Anders, MW ;
Dekant, W .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1998, 38 :501-537
[7]   Synthesis of novel Se-substituted selenocysteine derivatives as potential kidney selective prodrugs of biologically active selenol compounds: Evaluation of kinetics of beta-elimination reactions in rat renal cytosol [J].
Andreadou, I ;
Menge, WMPB ;
Commandeur, JNM ;
Worthington, EA ;
Vermeulen, NPE .
JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (10) :2040-2046
[8]   A functional link between RuBisCO-like protein of Bacillus and photosynthetic RuBisCO [J].
Ashida, H ;
Saito, Y ;
Kojima, C ;
Kobayashi, K ;
Ogasawara, N ;
Yokota, A .
SCIENCE, 2003, 302 (5643) :286-290
[9]  
AWATA S, 1995, BIOCHEM MOL BIOL INT, V35, P1331
[10]  
BACKLUND PS, 1982, J BIOL CHEM, V257, P4196