COENZYME-A METABOLISM IN VITAMIN-B-12-DEFICIENT RATS
COENZYME-A METABOLISM IN VITAMIN-B-12-DEFICIENT RATS
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DOI：
10.1093/jn/120.3.290
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发表时间：
1990-03-01
影响因子：
4.2
通讯作者：
STABLER, SP
中科院分区：
文献类型：
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作者：
BRASS, EP;TAHILIANI, AG;STABLER, SP
维生素B-12(钴胺)缺乏导致L-甲基丙二酰辅酶A(CoA)变位酶活性降低。在给予钴胺类似物羟基钴胺[c-内酰胺]或饮食中缺乏维生素B-12而导致功能性维生素B-12缺乏的大鼠中，研究了这种缺陷对细胞辅酶A池的影响。两种类型的维生素B-12缺乏都与甲基丙二酸血症有关(与对照组相比，血浆甲基丙二酸浓度增加100-300倍)，但总体燃料平衡是完整的。羟钴胺[c-内酰胺]处理的大鼠肝脏中总辅酶A(游离辅酶A加全酰辅酶A)的浓度比生理盐水处理的大鼠高三倍。辅酶A池分级显示，与对照组相比，羟钴胺[c-内酰胺]处理组大鼠的辅酶A、丙酰辅酶A、甲基丙二酰辅酶A、酸不溶辅酶A以及总辅酶A水平均高于对照组。在饮食中缺乏维生素B-12的情况下，无论是进食状态还是禁食状态，肝脏CoA含量都出现了类似的增加。为验证丙酰辅酶A和甲基丙二酰辅酶A可促进辅酶A生物合成的假说，研究了丙酸对正常大鼠肝细胞辅酶A生物合成的影响。在肝细胞系统中，丙酸(1 MM)可使[14C]泛酸(10微米)生成14C-CoA增加27%。当提供丁酸盐(1 MM)作为底物时，丙酸(10 MM)使[14C]CoA的形成增加了63%。α-酮丁酸酯，脱羧基丙酰-辅酶A，也增加肝细胞[14C]泛酸代谢。因此，维生素B-12缺乏与肝脏丙酰辅酶A和甲基丙二酰辅酶A的积累以及肝脏总辅酶A含量的增加有关。辅酶A总量的增加可能是由于辅酶A的生物合成增强所致，因为细胞辅酶A被隔离为代谢不良的酰基辅酶A。辅酶A生物合成的增加可能是维持细胞在酰基辅酶A积累条件下代谢的重要补偿机制。
Vitamin B-12 (cobalamin) deficiency results in decreased L-methylmalonyl-coenzyme A (CoA) mutase activity. The consequence of this defect on the cellular CoA pool was studied in rats with functional vitamin B-12 deficiency induced by administration of the cobalamin analogue hydroxy-cobalamin [c-lactam] or by dietary vitamin B-12 deficiency. Both types of vitamin B-12 deficiency were associated with methylmalonic acidemia (100-300-fold increases in plasma methylmalonic acid concentration compared with controls), but overall fuel homeostasis was intact. Liver from rats treated with hydroxy-cobalamin [c-lactam] contained a threefold greater concentration of total CoA (free CoA plus all acyl-CoA) compared with saline-treated rats. Fractionation of the CoA pool revealed higher levels of CoA, propionyl-CoA, methylmalonyl-CoA, acid-insoluble CoA, as well as total CoA in the rats treated with hydroxy-cobalamin [c-lactam] compared with controls. Similar increases in liver CoA content were seen in dietary vitamin B-12 deficiency in both the fed and fasted states. To examine the hypothesis that sequestration of hepatic CoA as propionyl-CoA and methylmalonyl-CoA could increase CoA biosynthesis, the effect of propionate on CoA biosynthesis was studied in hepatocytes isolated from control rats. Propionate (1 mM) increased the formation of 14C-CoA from [14C]pantothenate (10 .mu.M) by 27% in the hepatocyte system. When butyrate (1 mM) was provided as substrate, propionate (10 mM) increased [14C]CoA formation by 63%. .alpha.-Ketobutyrate, which is decarboxylated to propionyl-CoA, also increased hepatocyte [14C]pantothenate metabolism. Thus, vitamin B-12 deficiency is associated with hepatic accumulation of propionyl-CoA and methyl-malonyl-CoA, and an increase in hepatic total CoA content. This increase in total CoA content may result from enhanced biosynthesis of CoA because cellular CoA is sequestered as poorly metabolized acyl-CoA. The increase in CoA biosynthesis may be an important compensatory mechanism to maintain cellular metabolism under conditions of acyl-CoA accretion.