PMID- 11514561
OWN - NLM
STAT- MEDLINE
DCOM- 20011205
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 45
DP  - 2001 Nov 9
TI  - Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with 
      testosterone and NADP at 1.25-A resolution.
PG  - 42091-8
AB  - The first crystallographic structure of human type 3 3alpha-hydroxysteroid 
      dehydrogenase (3alpha-HSD3, AKR1C2), an enzyme playing a critical role in steroid 
      hormone metabolism, has been determined in complex with testosterone and NADP at 
      1.25-A resolution. The enzyme's 17beta-HSD activity was studied in comparison 
      with its 3alpha-HSD activity. The enzyme catalyzes the inactivation of 
      dihydrotestosterone into 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) as 
      well as the transformation of androstenedione into testosterone. Using our 
      homogeneous and highly active enzyme preparation, we have obtained 150-fold 
      higher 3alpha-HSD specificity as compared with the former reports in the 
      literature. Although the rat and the human 3alpha-HSDs share 81% sequence 
      homology, our structure reveals significantly different geometries of the active 
      sites. Substitution of the Ser(222) by a histidine in the human enzyme may compel 
      the steroid to adopt a different binding to that previously described for the rat 
      (Bennett, M. J., Albert, R. H., Jez, J. M., Ma, H., Penning, T. M., and Lewis, M. 
      (1997) Structure 5, 799-T812). Furthermore, we showed that the affinity for the 
      cofactor is higher in the human 3alpha-HSD3 than the rat enzyme due to the 
      presence of additional hydrogen bonds on the adenine moiety and that the cofactor 
      is present under its reduced form in the active site in our preparation.
FAU - Nahoum, V
AU  - Nahoum V
AD  - Oncology and Molecular Endocrinology Research Center, Laval University Medical 
      Center, Quebec, Quebec G1V 4G2, Canada.
FAU - Gangloff, A
AU  - Gangloff A
FAU - Legrand, P
AU  - Legrand P
FAU - Zhu, D W
AU  - Zhu DW
FAU - Cantin, L
AU  - Cantin L
FAU - Zhorov, B S
AU  - Zhorov BS
FAU - Luu-The, V
AU  - Luu-The V
FAU - Labrie, F
AU  - Labrie F
FAU - Breton, R
AU  - Breton R
FAU - Lin, S X
AU  - Lin SX
LA  - eng
PT  - Journal Article
DEP - 20010820
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Isoenzymes)
RN  - 3XMK78S47O (Testosterone)
RN  - 53-59-8 (NADP)
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.- (3-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.50 (3-alpha-Hydroxysteroid Dehydrogenase (B-Specific))
SB  - IM
MH  - 17-Hydroxysteroid Dehydrogenases/metabolism
MH  - 3-Hydroxysteroid Dehydrogenases/*chemistry/metabolism
MH  - 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
MH  - Binding Sites
MH  - Humans
MH  - Isoenzymes/*chemistry
MH  - NADP/*chemistry
MH  - Testosterone/*chemistry
EDAT- 2001/08/22 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/08/22 10:00
PHST- 2001/08/22 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/08/22 10:00 [entrez]
AID - S0021-9258(19)83066-1 [pii]
AID - 10.1074/jbc.M105610200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Nov 9;276(45):42091-8. doi: 10.1074/jbc.M105610200. Epub 2001 
      Aug 20.