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Structural and enzymatic properties of mammalian d-glutamate cyclase

Katane, Masumi, Ariyoshi, Makoto, Tateishi, Shuhei, Koiwai, Sachi, Takaku, Kaoruko, Nagai, Kenichiro, Nakayama, Kazuki, Saitoh, Yasuaki, Miyamoto, Tetsuya, Sekine, Masae, Mita, Masashi, Hamase, Kenji, Matoba, Satoaki, Homma, Hiroshi
Archives of biochemistry and biophysics 2018 v.654 pp. 10-18
adenosine diphosphate, adenosine triphosphate, cardiac output, catalytic activity, cations, enzyme activity, glutamic acid, heart, heart failure, manganese, mice, mitochondria, oligomerization, pH, risk
d-Glutamate cyclase (DGLUCY) is a unique enzyme that reversibly converts free d-glutamate to 5-oxo-d-proline and H2O. Mammalian DGLUCY is highly expressed in the mitochondrial matrix in the heart, and its downregulation disrupts d-glutamate and/or 5-oxo-d-proline levels, contributing to the onset and/or exacerbation of heart failure. However, detailed characterisation of DGLUCY has not yet been performed. Herein, the structural and enzymatic properties of purified recombinant mouse DGLUCY were examined. The results revealed a dimeric oligomerisation state, and both d-glutamate-to-5-oxo-d-proline and 5-oxo-d-proline-to-d-glutamate reactions were catalysed in a stereospecific manner. Catalytic activity is modulated by divalent cations and nucleotides including ATP and ADP. Interestingly, the presence of Mn2+ completely abolished the 5-oxo-d-proline-to-d-glutamate reaction but stimulated the d-glutamate-to-5-oxo-d-proline reaction. The optimum pH is ∼8.0, similar to that in the mitochondrial matrix, and the catalytic efficiency for d-glutamate is markedly higher than that for 5-oxo-d-proline. These findings suggest that DGLUCY functions as a metalloenzyme that degrades d-glutamate in the mitochondrial matrix in mammalian cells. The results also provide insight into the correlation between DGLUCY enzyme activity and the physiological and pathological roles of d-glutamate and 5-oxo-d-proline in cardiac function, which is of relevance to the risk of onset of heart failure.