Selective inhibition of protein disulfide isomerase by estrogens.
Protein disulfide isomerase (PDI) is a multifunctional microsomal enzyme that participates in the formation of protein disulfide bonds. PDI catalyzes the reduction of protein disulfide bonds in the presence of excess reduced glutathione and has been implicated in the reductive degradation of insulin; E. coli thioredoxin is homologous to two regions in PDI and can also degrade insulin. PDI activity, measured by 125I-insulin degradation or reactivation of randomly oxidized RNase in the presence of reduced glutathione, is non-competitively inhibited by estrogens; half-maximal inhibition was observed at approximately 100 nM estrogen. Other steroid hormones at 1 microM had little or no effect. PDI segment 120-163 (which corresponds to exon 3 of the PDI gene) and 182-230 have significant similarity with estrogen receptor segments 350-392 and 304-349, respectively, located in the estrogen binding domain but not with the steroid domains of the progesterone and glucocorticoid receptors or with thioredoxin, which is insensitive to estrogens. We propose the hypothesis that enzymes can acquire sensitivity to a hormone via exon shuffling to the enzyme gene from the DNA region coding for the hormone binding domain of the hormone's receptor.
Tsibris
J C
JC
Department of Obstetrics and Gynecology, University of Illinois College of Medicine, Chicago 60612.
Hunt
L T
LT
Ballejo
G
G
Barker
W C
WC
Toney
L J
LJ
Spellacy
W N
WN
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D003600:Cytosol / Q000201:enzymology; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007535:Isomerases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D008099:Liver / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D010920:Placenta / Q000201:enzymology; D019704:Protein Disulfide-Isomerases
D004967:Estrogens; D007328:Insulin; D007535:Isomerases; D019704:Protein Disulfide-Isomerases