Abstract：
:Protein modification generally occurs by addition to the amino acid side-chains of protein at the post-translational stage, for example, by enzymatic or chemical reactions after polypeptide synthesis. Recently, the recombinant hirudin analog CX-397, a potent thrombin inhibitor, was found to contain methylated Ile residues when it was overproduced by Escherichia coli in the absence of amino acids in the culture medium. The Ile derivatives, deduced to be beta-methylnorleucine [betaMeNle; (2S, 3S)-2-amino-3-methylhexanoic acid] by systematic chromatographic analysis, do not appear to be normal post-translational modifications of the protein because Ile has no functional group in its side-chain. We, therefore, propose that betaMeNle is biosynthesized by E. coli, activated by E. coli isoleucyl-tRNA synthetase (IleRS), then incorporated into the overproduced recombinant hirudin analog. The biosynthesis of betaMeNle in E. coli is thought to occur as follows: alpha-ketovalerate is synthesized from alpha-ketobutyrate by three Leu biosynthetic enzymes, alpha-isopropylmalate synthase (IPMS) (EC 4.1.3.12), alpha-isopropylmalate isomerase (ISOM) (EC 4.2.1.33) and beta-isopropylmalate dehydrogenase (IPMD) (EC 1.1.1.85), which have broad substrate specificities. alpha-Ketovalerate is then converted to alpha-keto-beta-methylcaproate by three Ile and Val biosynthetic enzymes, acetohydroxy acid synthase (AS) (EC 4.1.3.18), acetohydroxy acid isomeroreductase (IR) (EC 1.1.1.86) and dihydroxy acid dehydratase (DH) (EC 4.2.1.9). Finally, this is converted to betaMeNle by branched-chain amino acid transaminase (EC 2.6.1.42), one of the Ile and Val biosynthetic enzymes.
journal_name
J Pharm Biomed Analjournal_title
Journal of pharmaceutical and biomedical analysisauthors
Muramatsu R,Misawa S,Hayashi Hdoi
10.1016/s0731-7085(02)00703-3subject
Has Abstractpub_date
2003-04-01 00:00:00pages
979-87issue
5eissn
0731-7085issn
1873-264Xpii
S0731708502007033journal_volume
31pub_type
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