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The ASCT/SCS cycle fuels mitochondrial ATP and acetate production in Trypanosoma brucei.
Biochimica et Biophysica Acta (BBA) - Bioenergetics ( IF 4.3 ) Pub Date : 2020-08-04 , DOI: 10.1016/j.bbabio.2020.148283
Kota Mochizuki 1 , Daniel Ken Inaoka 2 , Muriel Mazet 3 , Tomoo Shiba 4 , Keisuke Fukuda 4 , Hana Kurasawa 4 , Yoann Millerioux 3 , Michael Boshart 5 , Emmanuel O Balogun 6 , Shigeharu Harada 4 , Kenji Hirayama 7 , Frédéric Bringaud 3 , Kiyoshi Kita 8
Affiliation  

Acetate:succinate CoA transferase (ASCT) is a mitochondrial enzyme that catalyzes the production of acetate and succinyl-CoA, which is coupled to ATP production with succinyl-CoA synthetase (SCS) in a process called the ASCT/SCS cycle. This cycle has been studied in Trypanosoma brucei (T. brucei), a pathogen of African sleeping sickness, and is involved in (i) ATP and (ii) acetate production and proceeds independent of oxygen and an electrochemical gradient. Interestingly, knockout of ASCT in procyclic form (PCF) of T. brucei cause oligomycin A-hypersensitivity phenotype indicating that ASCT/SCS cycle complements the deficiency of ATP synthase activity. In bloodstream form (BSF) of T. brucei, ATP synthase works in reverse to maintain the electrochemical gradient by hydrolyzing ATP. However, no information has been available on the source of ATP, although ASCT/SCS cycle could be a potential candidate. Regarding mitochondrial acetate production, which is essential for fatty acid biosynthesis and growth of T. brucei, ASCT or acetyl-CoA hydrolase (ACH) are known to be its source. Despite the importance of this cycle, direct evidence of its function is lacking, and there are no comprehensive biochemical or structural biology studies reported so far. Here, we show that in vitro–reconstituted ASCT/SCS cycle is highly specific towards acetyl-CoA and has a higher kcat than that of yeast and bacterial ATP synthases. Our results provide the first biochemical basis for (i) rescue of ATP synthase-deficient phenotype by ASCT/SCS cycle in PCF and (ii) a potential source of ATP for the reverse reaction of ATP synthase in BSF.



中文翻译:

ASCT / SCS循环为布鲁氏锥虫产生线粒体ATP和乙酸盐。

乙酸盐:琥珀酸CoA转移酶(ASCT)是一种线粒体酶,可催化乙酸盐和琥珀酰CoA的产生,并通过称为ASCT / SCS循环的过程将琥珀酰CoA合成酶(SCS)与ATP产生耦合。已在非洲昏睡病的病原体布鲁氏锥虫T. brucei)中研究了该循环,该循环涉及(i)ATP和(ii)乙酸盐的产生,并且独立于氧气和电化学梯度而进行。有趣的是,在的procyclic形式(PCF)ASCT的敲除布氏锥虫指示ASCT / SCS周期原因寡A-超敏反应表型补充ATP合酶活性的缺乏。T. brucei的血流形式(BSF),ATP合酶通过水解ATP逆向工作以维持电化学梯度。但是,尽管ASCT / SCS周期可能是一个潜在的候选者,但是关于ATP来源的信息尚无。关于线粒体乙酸酯的生产,其对于布鲁氏菌的脂肪酸生物合成和生长至关重要,ASCT或乙酰辅酶A水解酶(ACH)是其来源。尽管此循环很重要,但缺乏其功能的直接证据,并且迄今为止,尚无全面的生物化学或结构生物学研究报告。在这里,我们显示体外重建的ASCT / SCS循环对乙酰辅酶A具有高度特异性,并且具有较高的k cat比酵母和细菌ATP合酶要高。我们的结果为(i)通过PCF中的ASCT / SCS循环拯救ATP合酶缺陷型和(ii)ATP合酶在BSF中逆反应的潜在来源提供了第一个生化基础。

更新日期:2020-08-14
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