Putumbaka Saisuki, Schut Gerrit J, Thorgersen Michael P, Poole Farris L, Shao Nana, Rodionov Dmitry A, Adams Michael W W
Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602.
Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2411809121. doi: 10.1073/pnas.2411809121. Epub 2024 Dec 30.
is a dominant member of the human gut microbiome and produces short-chain fatty acids (SCFAs). These promote immune system function and inhibit inflammation, making this microbe important for human health. Lactate is a primary source of gut SCFAs but its utilization by has not been explored. We show that growing on lactate takes up added tungstate rather than molybdate and produces the SCFAs acetate and butyrate, but not propionate. The genes encoding an electron bifurcating, tungsten-containing oxidoreductase (WOR1) and a tungsten-containing formate dehydrogenase (FDH), along with an electron bifurcating lactate dehydrogenase (LCT), lactate permease, and enzymes of the propanediol pathway, are all up-regulated on lactate compared to growth on glucose. Lactate metabolism is controlled by a GntR-family repressor (LctR) and two global regulators, Rex and CcpA, where Rex in part controls W storage and tungstopyranopterin (Tuco) biosynthesis. Tuco-dependent riboswitches, along with CcpA, also control two iron transporters, consistent with the increased iron demand for many iron-containing enzymes, including WOR1 and FDH, involved in SCFA production. From intracellular aldehyde concentrations and the substrate specificity of WOR1, we propose that WOR1 is involved in detoxifying acetaldehyde produced during lactate degradation. Lactate to SCFA conversion by is clearly highly tungstocentric and tungsten might be an overlooked micronutrient in the human microbiome and in overall human health.
是人类肠道微生物群的主要成员,并产生短链脂肪酸(SCFAs)。这些短链脂肪酸可促进免疫系统功能并抑制炎症,使这种微生物对人类健康至关重要。乳酸是肠道SCFAs的主要来源,但其在 中的利用情况尚未得到研究。我们发现,在乳酸上生长的 会摄取添加的钨酸盐而非钼酸盐,并产生SCFAs乙酸盐和丁酸盐,但不产生丙酸盐。与在葡萄糖上生长相比,编码电子分叉的含钨氧化还原酶(WOR1)、含钨甲酸脱氢酶(FDH)、电子分叉乳酸脱氢酶(LCT)、乳酸通透酶以及丙二醇途径的酶的基因在乳酸上生长时均上调。乳酸代谢受GntR家族阻遏物(LctR)以及两个全局调节因子Rex和CcpA控制,其中Rex部分控制钨的储存和钨吡喃蝶呤(Tuco)的生物合成。Tuco依赖性核糖开关以及CcpA还控制两种铁转运蛋白,这与参与SCFA产生的许多含铁酶(包括WOR1和FDH)对铁的需求增加一致。根据细胞内醛浓度和WOR1的底物特异性,我们推测WOR1参与了乳酸降解过程中产生的乙醛的解毒。 通过乳酸向SCFA的转化显然高度以钨为中心,钨可能是人类微生物群和整体人类健康中被忽视的微量营养素。