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.
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
S S
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Kanji
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Kuohung
D C
DC
Labaree
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RB
Hochberg
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