Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.
Direct anabolic metabolism of three-carbon propionate to a six-carbon metabolite occurs in vivo across tissues and species.
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DOI：
10.1016/j.jlr.2022.100224
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发表时间：
2022-06
影响因子：
6.5
通讯作者：
Snyder, Nathaniel W.
中科院分区：
文献类型：
--
作者：
Doan, Mary T.;Neinast, Michael D.;Varner, Erika L.;Bedi, Kenneth C., Jr.;Bartee, David;Jiang, Helen;Trefely, Sophie;Xu, Peining;Singh, Jay P.;Jang, Cholsoon;Rame, J. Eduardo;Brady, Donita C.;Meier, Jordan L.;Marguiles, Kenneth B.;Arany, Zoltan;Snyder, Nathaniel W.
关键词：
哺乳动物中碳的合成代谢是通过一碳和二碳载体 S-腺苷甲硫氨酸和乙酰辅酶 A 介导的。相反，通过丙酸进行的三碳单位的合成代谢尚未被证明广泛发生。人们主要认为哺乳动物通过将丙酰辅酶A分流至琥珀酰辅酶A以进入TCA循环来氧化三碳短链脂肪酸丙酸酯。在这里，我们发现这可能不是绝对的，因为在哺乳动物中，丙酰辅酶A的一种非氧化命运是缩合成两个三碳单元，形成六碳反式2-甲基-2-戊烯酰辅酶A (2M2PE-CoA)。我们使用提供有限底物的纯化蛋白质提取物确认了该反应途径，并使用合成标准品通过 LC-MS 验证了产品。在稳定状态下输注 13C 标记的缬氨酸后进行的全身体内稳定同位素示踪中，发现 2M2PE-CoA 通过丙酰辅酶 A 在多种小鼠组织中形成，包括心脏、肾脏，以及较小程度的棕色脂肪组织、肝脏和胫骨前肌。使用离体同位素示踪，我们发现 2M2PE-CoA 也在与丙酸盐孵育的人心肌组织中形成有限程度。虽然这一途径的完整酶学仍有待阐明，但这些结果证实了人类和小鼠体内至少存在一种利用丙酸盐的合成代谢三至六碳反应。
Anabolic metabolism of carbon in mammals is mediated via the one- and two-carbon carriers S-adenosyl methionine and acetyl-coenzyme A. In contrast, anabolic metabolism of three-carbon units via propionate has not been shown to extensively occur. Mammals are primarily thought to oxidize the three-carbon short chain fatty acid propionate by shunting propionyl-CoA to succinyl-CoA for entry into the TCA cycle. Here, we found that this may not be absolute as, in mammals, one nonoxidative fate of propionyl-CoA is to condense to two three-carbon units into a six-carbon trans-2-methyl-2-pentenoyl-CoA (2M2PE-CoA). We confirmed this reaction pathway using purified protein extracts provided limited substrates and verified the product via LC-MS using a synthetic standard. In whole-body in vivo stable isotope tracing following infusion of 13C-labeled valine at steady state, 2M2PE-CoA was found to form via propionyl-CoA in multiple murine tissues, including heart, kidney, and to a lesser degree, in brown adipose tissue, liver, and tibialis anterior muscle. Using ex vivo isotope tracing, we found that 2M2PE-CoA also formed in human myocardial tissue incubated with propionate to a limited extent. While the complete enzymology of this pathway remains to be elucidated, these results confirm the in vivo existence of at least one anabolic three- to six-carbon reaction conserved in humans and mice that utilizes propionate.
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影响因子：
6.5
作者：
Snyder, Nathaniel W.;Basu, Sankha S.;Blair, Ian A.
通讯作者：
Blair, Ian A.
DOI：
10.1074/jbc.m116.720631
发表时间：
2016-06-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Perry RJ;Borders CB;Cline GW;Zhang XM;Alves TC;Petersen KF;Rothman DL;Kibbey RG;Shulman GI
通讯作者：
Shulman GI
影响因子：
82.9
作者：
Czech MP
通讯作者：
Czech MP
影响因子：
14.8
作者：
Wallace M;Green CR;Roberts LS;Lee YM;McCarville JL;Sanchez-Gurmaches J;Meurs N;Gengatharan JM;Hover JD;Phillips SA;Ciaraldi TP;Guertin DA;Cabrales P;Ayres JS;Nomura DK;Loomba R;Metallo CM
通讯作者：
Metallo CM
影响因子：
3.8
作者：
Weisfeld-Adams, James D.;Morrissey, Mark A.;Kirmse, Brian M.;Salveson, Bobbie R.;Wasserstein, Melissa P.;McGuire, Peter J.;Sunny, Sherlykutty;Cohen-Pfeffer, Jessica L.;Yu, Chunli;Caggana, Michele;Diaz, George A.
通讯作者：
Diaz, George A.