Balasubramaniam S, Goldstein J L, Brown M S
Proc Natl Acad Sci U S A. 1977 Apr;74(4):1421-5. doi: 10.1073/pnas.74.4.1421.
The activities of cytosolic 3-hydroxy-3-methylglutaryl coenzyme A synthase [3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase (CoA-acylating), EC 4.1.3.5] and microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase[mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34], two sequential enzymes in the cholesterol biosynthetic pathway, were shown to be regulated coordinately in the adrenal gland of the rat. When the plasma cholesterol level was lowered by administration of 4-aminopyrazolopyrimidine, a treatment known to enhance cholesterol synthesis in the adrenal, synthase activity in the gland rose by 14- to 29-fold and reductase activity rose by 50- to 100-fold. The subsequent intravenous infusion of low density lipoprotein restored the plasma cholesterol level and suppressed synthase and reductase activities in parallel. The activities of adrenal 3-hydroxy-3-methylglutaryl coenzyme A synthase and reductase were also shown to exhibit a coordinate pattern of diurnal variation with peaks in both enzymes achieved at the mid-point of the dark cycle. The activity of adrenal acetoacetyl coenzyme A thiolase (acetyl CoA acetyltransferase; acetyl-CoA:acetyl-CoA C-acetyltransferase, EC 2.3.1.9), the enzyme preceding the synthase in the cholesterol biosynthetic pathway, and the activity of adrenal mevalonate kinase (ATP:mevalonate 5-phosphotransferase, EC 2.7.1.36), the enzyme following the reductase, were not enhanced by cholesterol deprivation, and neither exhibited a pattern of diurnal variation. The coordinate control of 3-hydroxy-3-methylglutaryl CoA synthase and reductase in rat adrenal gland provides a model system to study the biochemical mechanism for the regulation of cholesterol synthesis in a tissue that uses cholesterol for the synthesis of steroid hormones.
胆固醇生物合成途径中的两种连续酶，即胞质3-羟基-3-甲基戊二酰辅酶A合酶[3-羟基-3-甲基戊二酰辅酶A乙酰乙酰辅酶A裂解酶（辅酶A酰化），EC 4.1.3.5]和微粒体3-羟基-3-甲基戊二酰辅酶A还原酶[甲羟戊酸：NADP +氧化还原酶（辅酶A酰化），EC 1.1.1.34]，在大鼠肾上腺中显示出协同调节作用。当通过给予4-氨基吡唑并嘧啶降低血浆胆固醇水平时（已知该处理可增强肾上腺中的胆固醇合成），肾上腺中合酶活性升高14至29倍，还原酶活性升高50至100倍。随后静脉输注低密度脂蛋白可恢复血浆胆固醇水平，并同时抑制合酶和还原酶活性。肾上腺3-羟基-3-甲基戊二酰辅酶A合酶和还原酶的活性还显示出昼夜变化的协同模式，两种酶的活性在黑暗周期的中点达到峰值。胆固醇生物合成途径中位于合酶之前的肾上腺乙酰乙酰辅酶A硫解酶（乙酰辅酶A乙酰转移酶；乙酰辅酶A：乙酰辅酶A C-乙酰转移酶，EC 2.3.1.9）的活性，以及位于还原酶之后的肾上腺甲羟戊酸激酶（ATP：甲羟戊酸5-磷酸转移酶，EC 2.7.1.36）的活性，在胆固醇缺乏时并未增强，且均未表现出昼夜变化模式。大鼠肾上腺中3-羟基-3-甲基戊二酰辅酶A合酶和还原酶的协同控制提供了一个模型系统，用于研究在利用胆固醇合成类固醇激素的组织中调节胆固醇合成的生化机制。
