SPECIFIC INHIBITION OF MITOCHONDRIAL FATTY-ACID OXIDATION BY 2-BROMOPALMITATE AND ITS COENZYME-A AND CARNITINE ESTERS
SPECIFIC INHIBITION OF MITOCHONDRIAL FATTY-ACID OXIDATION BY 2-BROMOPALMITATE AND ITS COENZYME-A AND CARNITINE ESTERS
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DOI：
10.1042/bj1290055
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发表时间：
1972-01-01
影响因子：
4.1
通讯作者：
TUBBS, PK
中科院分区：
文献类型：
--
作者：
CHASE, JFA;TUBBS, PK
1. 2-溴铝酸酯的辅酶a和肉碱酯是线粒体脂肪酸氧化的非常强大和特异性的抑制剂。2. 2-溴铝酰辅酶a，添加或由2-溴铝酸酯形成，抑制棕榈酸酯或棕榈酰辅酶a的肉毒碱依赖性氧化，但不抑制棕榈酰肉毒碱的氧化，由完整的肝脏线粒体。3. 2-溴棕榈酰肉碱抑制棕榈酰肉碱以及棕榈酸酯或棕榈酰辅酶a的氧化。对琥珀酸酯的氧化无影响，但对丙酮酸酯、2-氧葡萄糖酸酯和己酸酯的氧化有抑制作用；然而，这些底物的氧化（但不包括棕榈酸盐，棕榈酰辅酶a或棕榈酰肉碱）被肉碱恢复。4. 在受损线粒体中，添加2-溴铝二酰辅酶a可抑制棕榈酰肉碱氧化；丙酮酸氧化不受单独抑制剂的影响，但如果随后添加棕榈酰肉碱则会受损。5. 这些发现被解释如下。2-溴铝二酰辅酶a（以肉毒碱依赖的方式）使肉毒碱棕榈酰基转移酶池失活，该池可被外部酰基辅酶a获取。这导致抑制棕榈酸酯或棕榈酰辅酶a氧化。在完整的线粒体中，添加的酰基辅酶A无法进入另一个肉毒碱棕榈酰基转移酶池，它可以在基质内从外部的2-溴铝酰基肉毒碱生成溴铝酰基辅酶A；这个反应是可逆的。这种内部的2-溴铝二酰辅酶a使长链β氧化失活（如果线粒体受损，添加的2-溴铝二酰辅酶a也会失活），它的形成也会隔离线粒体内的辅酶a。由于丙酮酸和2-氧葡萄糖酸脱氢酶共享这种辅酶a，因此它们的底物的氧化被2-溴铝酰基肉毒碱抑制，除非游离肉毒碱可以作为长链酰基的“沉淀”。6. 这些效果与其他脂肪酸氧化抑制剂报道的效果进行了比较。
1. The CoA and carnitine esters of 2-bromopalmitate are extremely powerful and specific inhibitors of mitochondrial fatty acid oxidation. 2. 2-Bromopalmitoyl-CoA, added as such or formed from 2-bromopalmitate, inhibits the carnitine-dependent oxidation of palmitate or palmitoyl-CoA, but not the oxidation of palmitoylcarnitine, by intact liver mitochondria. 3. 2-Bromopalmitoylcarnitine inhibits the oxidation of palmitoylcarnitine as well as that of palmitate or palmitoyl-CoA. It has no effect on succinate oxidation, but inhibits that of pyruvate, 2-oxoglutarate or hexanoate; however, the oxidation of these substrates (but not of palmitate, palmitoyl-CoA or palmitoyl-carnitine) is restored by carnitine. 4. In damaged mitochondria, added 2-bromopalmitoyl-CoA does inhibit palmitoylcarnitine oxidation; pyruvate oxidation is unaffected by the inhibitor alone, but is impaired if palmitoylcarnitine is subsequently added. 5. The findings have been interpreted as follows. 2-Bromopalmitoyl-CoA inactivates (in a carnitine-dependent manner) a pool of carnitine palmitoyltransferase which is accessible to external acyl-CoA. This results in inhibition of palmitate or palmitoyl-CoA oxidation. A second pool of carnitine palmitoyltransferase, inaccessible to added acyl-CoA in intact mitochondria, can generate bromopalmitoyl-CoA within the matrix from external 2-bromopalmitoylcarnitine; this reaction is reversible. Such internal 2-bromopalmitoyl-CoA inactivates long-chain β-oxidation (as does added 2-bromopalmitoyl-CoA if the mitochondria are damaged) and its formation also sequesters intramitochondrial CoA. Since this CoA is shared by pyruvate and 2-oxoglutarate dehydrogenases, the oxidation of their substrates is depressed by 2-bromopalmitoylcarnitine, unless free carnitine is available to act as a ‘sink’ for long-chain acyl groups. 6. These effects are compared with those reported for other inhibitors of fatty acid oxidation.