Regiospecific esterification of estrogens by lecithin:cholesterol acyltransferase.
Lecithin:cholesterol acyltransferase (LCAT), the enzyme that esterifies cholesterol in blood, also esterifies other steroids at the 3beta-hydroxyl. These steroids, like cholesterol, are delta5-3beta-hydroxysteroids, such as pregnenolone and dehydroepiandrosterone. One unusual LCAT substrate is the estrogen, estradiol, which is esterified at the 17beta-hydroxyl. The esterification of estradiol by LCAT has been reported to produce a powerful antioxidant that protects low density lipoprotein (LDL) from oxidation. We investigated the substrate specificity of LCAT, comparing the esterification of four different steroids (estradiol, estriol, testosterone, and 5-androstene-3beta, 17beta-diol) by human LCAT in blood and by acyl-coenzyme A:acyltransferase in tissue (placenta and fat). Estradiol was esterified only at the D ring 17beta-hydroxyl group in both blood and tissue. In contrast, although testosterone has a D ring structure identical to that of estradiol, and it was esterified at the 17beta-hydroxyl by acyl-coenzyme A:acyltransferase in tissue, it was not esterified by LCAT. When 5-androstenediol was the substrate in the tissues, both the 3beta- and 17beta-esters were synthesized, but the major product was the 17beta-ester. Conversely, although 5-androstenediol was an excellent substrate for LCAT, only the 3beta-hydroxyl was esterified. No 17beta-ester was formed. The comparison of the esterification of estriol by acyl-coenzyme A:acyltransferase and LCAT was also surprising. In the tissues, estriol is esterified at both D ring hydroxyls, and both are esterified about equally. Although estriol is an extremely polar estrogen, it is esterified by LCAT, albeit at a very slow rate. Although again both D ring hydroxyls were esterified, the LCAT esterification site was mainly at the 17beta-hydroxyl. Esterification of estriol at the 17beta-hydroxyl in preference to the 16alpha-hydroxyl is especially striking, because the 17beta-hydroxyl group is sterically shielded by the C-18 methyl group, making esterification at this position energetically much more difficult. Furthermore, these studies demonstrate that esterification of the 17beta-hydroxyl group by LCAT is unique to estrogens. It suggests that this unusual regiospecific esterification of C-17 of the estrogens underlies a distinct stereochemical requirement for the powerful antioxidant action that has reported for the estradiol esters formed by LCAT.
Kanji
S S
SS
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Kuohung
W
W
Labaree
D C
DC
Hochberg
R B
RB
D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology; D015114:Androstenediol / Q000378:metabolism; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004951:Esterification; D004958:Estradiol / Q000378:metabolism; D004964:Estriol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism
D000214:Acyl Coenzyme A; D004967:Estrogens; D013739:Testosterone; D004958:Estradiol; D015114:Androstenediol; D004228:Dithionitrobenzoic Acid; D000217:Acyltransferases; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D004964:Estriol