VioC is a non-heme iron, α-ketoglutarate-dependent oxygenase that catalyzes the formation of 3S-hydroxy-L-arginine during viomycin biosynthesis
VioC is a non-heme iron, α-ketoglutarate-dependent oxygenase that catalyzes the formation of 3S-hydroxy-L-arginine during viomycin biosynthesis
复制标题
DOI：
10.1002/cbic.200400082
复制
发表时间：
2004-09-06
期刊：
影响因子：
3.2
通讯作者：
Zabriskie, TM
中科院分区：
文献类型：
--
作者：
Yin, XH;Zabriskie, TM
The tuberactinomycins (Tbms) are nonribosomal peptide antibiotics produced by various species of Nocardia and Streptomyces and include viomycin (1, tuberactinomycin B) and the capreomycins (2).[1–3] These highly basic compounds exhibit a range of biological activities that center on their ability to bind RNA and, most importantly, disturb bacterial protein biosynthesis.[4–6] Both 1 and 2 show potent activity against Mycobacterium tuberculosis but associated ototoxicity and nephrotoxicity limit their clinical use to the treatment of recurring or multidrug-resistant M. tuberculosis infections. To gain a better understanding of Tbm biosynthesis, particularly the formation of the nonproteinogenic amino acid residues, and to facilitate genetic and combinatorial-biosynthesis approaches to generate less toxic Tbm analogues, we recently cloned the gene cluster that directs viomycin biosynthesis from Streptomyces vinaceus ATCC 11861.[7] During our initial analysis of the viomycin gene cluster, we identified an open reading frame predicted to encode a non-heme iron, α-ketoglutarate-dependent oxygenase and, through gene-disruption experiments, correlated the function of this gene with the production of 1. Sequence comparison of the S. vinaceus oxygenase with enzymes of proven function revealed a close similarity with clavaminate synthase (CS), a trifunctional oxygenase involved in the conversion of the arginine derivative deoxyguanidinoproclavaminic acid to the β-lactamase inhibitor clavulanic acid.[8, 9] This suggested that the S. vinaceus enzyme may function in the oxidative transformation of L-Arg to capreomycidine (3), the characteristic arginine-derived residue present in all Tbms. Thomas et al. have also identified and sequenced the entire viomycin cluster and proposed that this oxygenase gene, termed vioC, encodes an arginine β-hydroxylase.[10] Because CS catalyzes a β-hydroxylation, an oxidative cyclization, and a dehydrogenation, it seemed plausible that VioC would promote one or more of these reactions in the formation of 3. Previous isotope-incorporation experiments in vivo with the capreomycin producer established that H-2 and one H-3 of arginine are lost in the conversion to 3.[11][a] Dr. X. Yin, Prof. TM Zabriskie Department of Pharmaceutical Sciences, Oregon State University Corvallis, Oregon 97331-3507 (USA) E-mail: mark. zabriskie@ oregonstate. edu [b] Prof. TM Zabriskie Program in Molecular and Cellular Biology, Oregon State University Corvallis, Oregon 97331-3507 (USA) Fax:(+ 1) 541-737-3999
