Kelley R I, Kratz L
Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA.
Pediatr Res. 1995 May;37(5):671-4. doi: 10.1203/00006450-199505000-00020.
The branched-chain organic acid, 3-methylglutaconic acid, is an intermediate (as the CoA thioester) in the leucine degradative pathway as well as the mevalonate shunt, a pathway that links isoprenoid metabolism with mitochondrial acetyl-CoA metabolism. Because the majority of patients with abnormal 3-methylglutaconic aciduria or acidemia appear to have normal leucine metabolism, we have speculated that some patients with 3-methylglutaconic aciduria may have defects of polyisoprenoid or sterol biosynthesis leading to overflow of isoprenoid precursors to 3-methylglutaconate via the mevalonate shunt. We therefore measured plasma levels of 3-methylglutaconic acid in patients with a known defect of sterol biosynthesis, Smith-Lemli-Opitz syndrome, and found that the patients with the lowest cholesterol levels had abnormally increased plasma levels of 3-methylglutaconic acid, similar in magnitude to those of patients with idiopathic 3-methylglutaconic aciduria. This finding suggests that some patients with unexplained 3-methylglutaconic aciduria may have defects of isoprenoid or sterol biosynthesis underlying their abnormal organic aciduria.
支链有机酸3-甲基戊二酸是亮氨酸降解途径以及甲羟戊酸分流途径中的一种中间体（以辅酶A硫酯形式存在），甲羟戊酸分流途径将类异戊二烯代谢与线粒体乙酰辅酶A代谢联系起来。由于大多数3-甲基戊二酸尿症或酸血症患者的亮氨酸代谢似乎正常，我们推测一些3-甲基戊二酸尿症患者可能存在多聚异戊二烯或甾醇生物合成缺陷，导致类异戊二烯前体通过甲羟戊酸分流途径溢流至3-甲基戊二酸。因此，我们测量了已知甾醇生物合成缺陷患者——史密斯-勒米-奥皮茨综合征患者的血浆3-甲基戊二酸水平，发现胆固醇水平最低的患者血浆3-甲基戊二酸水平异常升高，升高幅度与特发性3-甲基戊二酸尿症患者相似。这一发现表明，一些不明原因的3-甲基戊二酸尿症患者的异常有机酸尿症可能是由类异戊二烯或甾醇生物合成缺陷所致。
