Journal
BIOCHEMICAL JOURNAL
Volume 462, Issue -, Pages 163-171Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20140220
Keywords
bile acid deficiency; cholesterol metabolism; rate determining step; stopped-flow
Categories
Funding
- National Institutes for Health (NIH) [R01-DK47015, P30 ES013508, F32-DK089827]
Ask authors/readers for more resources
Human AKR1D1 (steroid 5 beta-reductase/aldo-keto reductase 1D1) catalyses the stereospecific reduction of double bonds in Delta(4)-3-oxosteroids, a unique reaction that introduces a 900 bend at the A/B ring fusion to yield 5 beta-dihydrosteroids. AKR1D1 is the only enzyme capable of steroid 5 beta-reduction in humans and plays critical physiological roles. In steroid hormone metabolism, AKR1D1 serves mainly to inactivate the major classes of steroid hormones. AKR1D1 also catalyses key steps of the biosynthetic pathway of bile acids, which regulate lipid emulsification and cholesterol homoeostasis. Interestingly, AKR1D1 displayed a 20-fold variation in the k(cat) values, with steroid hormone substrates (e.g. aldosterone, testosterone and cortisone) having significantly higher k(cat) values than steroids with longer side chains (e.g. 7 alpha-hydroxycholestenone, a bile acid precursor). Transient kinetic analysis revealed striking variations up to two orders of magnitude in the fate of the chemistry step (k(chem)), which resulted in different rate determining steps for the fast and slow substrates. By contrast, similar K-d values were observed for representative fast and slow substrates, suggesting similar rates of release for different steroid products. The release of NADP(+) was shown to control the overall turnover for fast substrates, but not for slow substrates. Despite having high k(chem), values with steroid hormones, the kinetic control of AKR1D1 is consistent with the enzyme catalysing the slowest step in the catabolic sequence of steroid hormone transformation in the liver. The inherent slowness of the conversion of the bile acid precursor by AKR1D1 is also indicative of a regulatory role in bile acid synthesis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available