Crystal structure of <i>O</i>‐ureidoserine racemase found in the <scp>d</scp>‐cycloserine biosynthetic pathway

Oda, Kosuke; Sakaguchi, Takemasa; Matoba, Yasuyuki

doi:10.1002/prot.26290

Cited by 2 publications

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“…11 L-NOHA is produced by the hydroxylation of L-arginine (L-Arg) by the heme-containing enzyme, DcsA. 12 The generated Oureido-L-serine is racemized by DcsC 9,13,14 and subsequently cyclized with the help of DcsG, which is a member of the ATP-grasp fold family enzymes. 9,15 Arginase is a binuclear manganese enzyme that catalyzes the hydrolysis of L-Arg to produce L-ornithine (L-Orn) and urea (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

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Catalytic mechanism of DcsB: Arginase framework used for hydrolyzing its inhibitor

2022

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DcsB, an enzyme produced from the d‐cycloserine biosynthetic gene cluster, displays moderate similarity to arginase in the sequence and three‐dimensional structure. Arginase is a ubiquitous enzyme hydrolyzing l‐arginine to generate l‐ornithine and urea, whereas DcsB hydrolyzes Nω‐hydroxy‐l‐arginine (l‐NOHA), an arginase inhibitor, to generate l‐ornithine and hydroxyurea. We determined the crystal structure of DcsB associated with l‐ornithine and that with the tetrahedral derivative of 2(S)‐amino‐6‐boronohexanoic acid, whose boron atom forms a covalent bond with an oxygen atom bridging two manganese ions at the active center. The substrate‐binding pocket of DcsB is narrower than that of arginase, suggesting that DcsB is unsuitable for the binding of l‐NOHA in an inhibitory manner. The transition state‐like structure demonstrated that Asp210 and Glu241 have a role to trap a positively charged ion near the dimanganese cluster. Kinetic analysis using the mutated DcsB showed that the enzyme employs different catalytic mechanisms under the neutral and alkaline pH conditions. Glu241 in DcsB is likely involved in the recognition of the hydroxyguanidino group of l‐NOHA, whereas Asp210, in cooperation with Glu241, seems to contribute to the reactivity toward the protonated l‐NOHA, which is a preferable species under the neutral pH conditions. After entering of the protonated l‐NOHA to the substrate‐binding pocket of DcsB, a hydronium ion may be trapped at the positive ion‐binding site. Then, the ion serves as a specific acid catalyst to facilitate the collapse of the tetrahedral intermediate of l‐NOHA.

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Section: Introductionmentioning

confidence: 99%

“… 11 l ‐NOHA is produced by the hydroxylation of l ‐arginine ( l ‐Arg) by the heme‐containing enzyme, DcsA 12 . The generated O ‐ureido‐ l ‐serine is racemized by DcsC 9,13,14 and subsequently cyclized with the help of DcsG, which is a member of the ATP‐grasp fold family enzymes 9,15 …”

Section: Introductionmentioning

confidence: 99%