Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells.
Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells.
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Carnitine octanoyltransferase对于在哺乳动物细胞中将外源性乙酰基-L-肉碱同化成乙酰辅酶A中很重要。
DOI：
10.1016/j.jbc.2022.102848
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发表时间：
2023-03
影响因子：
4.8
通讯作者：
Khosla, Chaitan
中科院分区：
文献类型：
--
作者：
Hsu, Jake;Fatuzzo, Nina;Weng, Nielson;Michno, Wojciech;Dong, Wentao;Kienle, Maryline;Dai, Yuqin;Pasca, Anca;Abu-Remaileh, Monther;Rasgon, Natalie;Bigio, Benedetta;Nasca, Carla;Khosla, Chaitan
在真核生物中，肉碱以其将酯化脂肪酸通过线粒体膜进行β氧化的能力而闻名。它还以乙酰左旋肉碱（LAC）的形式返回细胞质，产生一些用于翻译后蛋白质修饰和脂质生物合成的乙酰基。虽然临床研究了膳食中LAC的补充，但其对细胞代谢的影响尚不清楚。为了解释外源性LAC如何影响哺乳动物细胞代谢，我们合成了同位素标记形式的LAC及其类似物。在葡萄糖限制的U87MG胶质瘤细胞培养中，外源性LAC比哺乳动物中主要的循环酮体β-羟基丁酸对细胞内乙酰辅酶a池的贡献更大。外源性13C2-acetyl-L-carnitine对U87MG细胞中脂肪酸的强标记表明，大多数lac衍生的乙酰辅酶a是胞质性的。我们发现d3-acetyl-L-carnitine的加入增加了用于细胞质翻译后修饰的乙酰辅酶a的供应，因为它对乙酰辅酶a羧化酶有很强的动力学同位素效应，乙酰辅酶a羧化酶是脂肪酸生物合成的第一步。令人惊讶的是，虽然胞浆肉碱乙酰转移酶被认为是催化乙酰基从LAC转移到辅酶A，但CRAT−/−U87MG细胞将外源LAC同化为乙酰辅酶A的能力并未受损。我们确定肉碱辛烷基转移酶是这一过程中的关键酶，暗示过氧化物酶体在有效利用LAC中的作用。我们的工作为进一步的生化研究打开了大门，为某些葡萄糖饥饿细胞提供乙酰辅酶a的新途径。
In eukaryotes, carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for β-oxidation. It also returns to the cytoplasm, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for posttranslational protein modification and lipid biosynthesis. While dietary LAC supplementation has been clinically investigated, its effects on cellular metabolism are not well understood. To explain how exogenous LAC influences mammalian cell metabolism, we synthesized isotope-labeled forms of LAC and its analogs. In cultures of glucose-limited U87MG glioma cells, exogenous LAC contributed more robustly to intracellular acetyl-CoA pools than did β-hydroxybutyrate, the predominant circulating ketone body in mammals. The fact that most LAC-derived acetyl-CoA is cytosolic is evident from strong labeling of fatty acids in U87MG cells by exogenous 13C2-acetyl-L-carnitine. We found that the addition of d3-acetyl-L-carnitine increases the supply of acetyl-CoA for cytosolic posttranslational modifications due to its strong kinetic isotope effect on acetyl-CoA carboxylase, the first committed step in fatty acid biosynthesis. Surprisingly, whereas cytosolic carnitine acetyltransferase is believed to catalyze acetyl group transfer from LAC to coenzyme A, CRAT−/− U87MG cells were unimpaired in their ability to assimilate exogenous LAC into acetyl-CoA. We identified carnitine octanoyltransferase as the key enzyme in this process, implicating a role for peroxisomes in efficient LAC utilization. Our work has opened the door to further biochemical investigations of a new pathway for supplying acetyl-CoA to certain glucose-starved cells.
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影响因子：
3.9
作者：
Baker A;Carrier DJ;Schaedler T;Waterham HR;van Roermund CW;Theodoulou FL
通讯作者：
Theodoulou FL
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影响因子：
9
作者：
Qu Q;Zeng F;Liu X;Wang QJ;Deng F
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Deng F
影响因子：
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作者：
Snyder, Nathaniel W.;Basu, Sankha S.;Blair, Ian A.
通讯作者：
Blair, Ian A.
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
4.1
作者：
Altamimi, Tariq R.;Thomas, Panakkezhum D.;Lopaschuk, Gary D.
通讯作者：
Lopaschuk, Gary D.