한빛사논문
- 조회318
Yong-Uk Lee 1, Bennett W. Fox 2, Rui Guo 1,3, Brian J. Curtis 2, Jingfang Yu 2, Sookyung Kim 4, Shivani Nanda 1,5,6, Victor Baumann 2, L. Safak Yilmaz 1, Cole M. Haynes 4, Frank C. Schroeder 2 & Albertha J. M. Walhout 1,*
1Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
2Boyce Thompson Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
3Institute of Environment, Resource, Soil and Fertilizer, Zhejiang Academy of Agricultural Science, Hangzhou, P. R. China.
4Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
5Present address: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
6Present address: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
*Corresponding author: correspondence to Albertha J. M. Walhout
Abstract
In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host–bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-12)
- 국외 연구진
- 생명과학 > 분자생물학
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