Close kinship of human 20α‐hydroxysteroid dehydrogenase gene with three aldo‐keto reductase genes

Abstract

Background: 20a-Hydroxysteroid dehydrogenase (HSD) is a member of the aldo-keto reductase (AKR) superfamily and catalyses the reaction of progesterone to the inactive form 20a-hydroxyprogesterone. Progesterone plays an important role in the maintenance of pregnancy, and, in rodents, plasma progesterone levels decrease abruptly just before parturition. The induction of 20a-HSD is thought to be responsible for the decrease in plasma progesterone at term. High homology between human 20a-HSD [AKR 1C1] cDNA with other AKRs had caused dif®culty in gene isolation and expression analysis. Thus, the metabolism of progesterone in the human reproductive system remained unclear.

Substrate Specificity of Human 3(20).ALPHA.-Hydroxysteroid Dehydrogenase for Neurosteroids and Its Inhibition by Benzodiazepines.

“…21) This value is much lower than that for 5a-DHP in this study and those for other hydroxysteroids and ketosteroids determined by the spectrophotometric and radiometric assays. [6][7][8]11,17) Our data that showed no significant difference in the kinetic constants for 5a-and 5b-isomers of THP or DHP also exclude the possibility that the 5a-isomer of DHP is a specifically good substrate for AKR1C2. To clarify the discrepancy in the K m value for 5a-DHP between the previous and present studies, we analyzed the products of 5a-DHP reduction by AKR1C2, because the radiometric assay measured 3a,5a-THP separated by TLC after 20 min-incubation.…”

“…13,14) Analyses of mRNA species for AKR1C isoenzymes in human tissues have shown that the isoenzymes, except for liver-specific AKR1C4, are expressed ubiquitously. 7,[9][10][11][14][15][16][17] In human brain AKR1C1, AKR1C2 and AKR1C3 are highly expressed, 11,16) although the distribution and localization of the enzymes in the brain remain unknown. These findings have suggested not only the roles of AKR1C1-AKR1C3 in the synthesis of the 3a,5a-THP and 3a,5a-THDOC, but also a possibility that the isoenzymes convert the potent neurosteroids to weak neurosteroids, 3a,20a-dihydroxypregnanes, 2,3) by exhibiting their 20a-HSD activities.…”

Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women

“…AKR1C enzymes are highly homologous. 3␣-HSD-3 shares 98% amino acid identity with 20␣-HSD, and its identity with type 5 17␤-HSD is 88% (14,25,28). However, despite being nearly identical in amino acid sequence, these enzymes have distinct substrate specificities, with 3␣-HSD-3 being involved mostly in androgen inactivation (reaction of DHT to 5␣-androstane-3␣,17␤-diol) and 20␣-HSD as well as type 5 17␤-HSD being involved mostly in the formation of 20␣-hydroxyprogesterone from progesterone.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…AKR1C3 (PGF synthase) has an active site which is capable of reducing both the endoperoxide group of PGH 2 and the aldehyde group of PGD 2 . The PGF synthase protein is abundant in the lung and the spleen ) although transcripts of the gene have also been detected in kidney, skeletal muscle, leukocytes, uterus, and liver by RT-PCR (Nishizawa et al, 2000). Other reductases with PGD 2 11-ketoreductase activity have been localized to the liver, heart and other organs, however, the identity of those enzymes remains unclear and they could be other members of the AKR1C family.…”