Pipecolic Acid Hydroxylases: A Monophyletic Clade among cis-Selective Bacterial Proline Hydroxylases that Discriminates L-Proline

被引:29
作者
Mattay, Johanna [1 ]
Huettel, Wolfgang [1 ]
机构
[1] Univ Freiburg, Inst Pharmaceut Sci, Albertstr 25, D-79104 Freiburg, Germany
关键词
biocatalysis; enzymes; hydroxylation; iron; structure-activity relationships; 4-HYDROXYLASE; 3-HYDROXYLASE; PURIFICATION; FAMILY; ENZYME;
D O I
10.1002/cbic.201700187
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
Proline hydroxylases are iron(II)/2-oxoglutarate-dependent enzymes that hydroxylate L-proline and derivatives, such as L-pipecolic acid, which is the six-membered-ring homologue of L-proline. It has been established that there is a distinct group of conserved bacterial enzymes that hydroxylate L-pipecolic acid and trans-3- and trans-4-methyl-L-proline, but virtually no L-proline. This allows the organism to produce hydroxyproline congeners without hydroxylation of the physiologically omnipresent L-proline. In vitro conversions showed that the substrate spectrum of the pipecolic acid hydroxylases GetF (from a Streptomyces sp.; producer of the tetrapeptide antibiotic GE81112) and PiFa (from Frankia alni) overlaps that of proline hydroxylases, except for the nonacceptance of L-proline and smaller homologues. Distinct and conserved residues were determined for both types of enzymes. However, site-directed mutagenesis in GetF did not yield variants that accepted L-proline; this suggested a complex interaction of several residues around the active site, which resulted in delicate changes in substrate specificity. This is supported by substrate docking in a homology model of GetF, which revealed an altered orientation for L-proline relative to that of preferred substrates.
引用
收藏
页码:1523 / 1528
页数:6
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