Inherent steroid 17,20-lyase activity in defunct cytochrome P450 17A enzymes

doi:10.1074/jbc.RA117.000504

QIBEBT-IR

	Inherent steroid 17,20-lyase activity in defunct cytochrome P450 17A enzymes
	Gonzalez, Eric 1; Johnson, Kevin M.1,4; Pallan, Pradeep S.1; Phan, Thanh T. N.1; Zhang, Wei 1,5; Lei, Li 1; Wawrzak, Zdzislaw 2; Yoshimoto, Francis K.3; Egli, Martin 1; Guengerich, F. Peter 1
	2018-01-12
发表期刊	JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN	0021-9258
卷号	293 期号:2 页码:541-556
摘要	Cytochrome P450 (P450) 17A1 catalyzes the oxidations of progesterone and pregnenolone and is the major source of androgens. The enzyme catalyzes both 17-hydroxylation and a subsequent 17,20-lyase reaction, and several mechanisms have been proposed for the latter step. Zebrafish P450 17A2 catalyzes only the 17-hydroxylations. We previously reported high similarity of the crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1. Five residues near the heme, which differed, were changed. We also crystallized this five-residue zebrafish P450 17A1 mutant, and the active site still resembled the structure in the other proteins, with some important differences. These P450 17A1 and 17A2 mutants had catalytic profiles more similar to each other than did the wildtype proteins. Docking with these structures can explain several minor products, which require multiple enzyme conformations. The 17-hydroperoxy (OOH) derivatives of the steroids were used as oxygen surrogates. Human P450 17A1 and zebrafish P450s 17A1 and P450 17A2 readily converted these to the lyase products in the absence of other proteins or cofactors (with catalytically competent kinetics) plus hydroxylated 17-hydroxysteroids. The 17-OOH results indicate that a Compound I (FeO3+) intermediate is capable of formation and can be used to rationalize the products. We conclude that zebrafish P450 17A2 is capable of lyase activity with the 17-OOH steroids because it can achieve an appropriate conformation for lyase catalysis in this system that is precluded in the conventional reaction.
文章类型	Article
关键词	Biomimetic Models
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
DOI	10.1074/jbc.RA117.000504
关键词[WOS]	TERTIARY ALPHA-KETOLS ; C-13 NMR-SPECTRA ; PROSTATE-CANCER ; ANDROGEN FORMATION ; ADRENAL-CORTEX ; P450 REDUCTASE ; SIDE-CHAIN ; BIOSYNTHESIS ; CYP17 ; B(5)
收录类别	SCI
语种	英语
WOS研究方向	Biochemistry & Molecular Biology
项目资助者	National Institutes of Health(R01 GM118122 ; R01 GM103937 ; T32 ES007028)
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000419915400011
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
引用统计
文献类型	期刊论文
条目标识符	http://ir.qibebt.ac.cn/handle/337004/10534
专题	中国科学院青岛生物能源与过程研究所
通讯作者	Guengerich, F. Peter
作者单位	1.Vanderbilt Univ, Dept Biochem, Sch Med, 638B Robinson Res Bldg,2200 Pierce Ave, Nashville, TN 37232 USA 2.Argonne Natl Lab, Adv Photon Source, Life Sci Collaborat Access Team, Sect 21, Argonne, IL 60439 USA 3.Univ Texas San Antonio, Dept Chem, San Antonio, TX 78249 USA 4.Genentech Inc, Dept Drug Metab & Pharmacokinet, 1 DNA Way, San Francisco, CA 94080 USA 5.Chinese Acad Sci, Qingdao Inst Bioenergy & Bioproc Technol, 189 Songling Rd, Qingdao 266000, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Gonzalez, Eric,Johnson, Kevin M.,Pallan, Pradeep S.,et al. Inherent steroid 17,20-lyase activity in defunct cytochrome P450 17A enzymes[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(2):541-556.
APA	Gonzalez, Eric.,Johnson, Kevin M..,Pallan, Pradeep S..,Phan, Thanh T. N..,Zhang, Wei.,...&Guengerich, F. Peter.(2018).Inherent steroid 17,20-lyase activity in defunct cytochrome P450 17A enzymes.JOURNAL OF BIOLOGICAL CHEMISTRY,293(2),541-556.
MLA	Gonzalez, Eric,et al."Inherent steroid 17,20-lyase activity in defunct cytochrome P450 17A enzymes".JOURNAL OF BIOLOGICAL CHEMISTRY 293.2(2018):541-556.