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一种新型的 3-羟类固醇脱氢酶，可调节生殖发育和寿命。

A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity.

机构信息

Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America.

出版信息

PLoS Biol. 2012;10(4):e1001305. doi: 10.1371/journal.pbio.1001305. Epub 2012 Apr 10.

DOI:10.1371/journal.pbio.1001305
PMID:22505847
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3323522/
Abstract

Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans.

摘要

内源性小分子代谢物调节动物寿命，成为影响健康和寿命的新方法。在秀丽隐杆线虫中，被称为达法克罗酸（DA）的胆酸样类固醇通过保守的核激素受体 DAF-12 调节发育时间和寿命，DAF-12 是哺乳动物甾醇调节受体 LXR 和 FXR 的同源物。我们使用代谢遗传学、质谱和生化方法，鉴定了 DA 生物合成中的新活性，并将一种进化上保守的短链脱氢酶 DHS-16 鉴定为新型 3-羟甾醇脱氢酶。通过调节 DA 的产生，DHS-16 控制 DAF-12 的活性，从而响应来自性腺的信号来调节寿命。我们阐明了秀丽隐杆线虫胆酸生物合成途径，揭示了新型配体的可能性以及与其他动物惊人的生化保守性，这可能为操纵后生动物的寿命提供新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/025a5d29ddd6/pbio.1001305.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/30eb243e8506/pbio.1001305.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/a2d412573cb9/pbio.1001305.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/98ae55e70cc7/pbio.1001305.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/18aaa1b87a36/pbio.1001305.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/23dad7d3d694/pbio.1001305.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/21072a795cd3/pbio.1001305.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/025a5d29ddd6/pbio.1001305.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/30eb243e8506/pbio.1001305.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/a2d412573cb9/pbio.1001305.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/98ae55e70cc7/pbio.1001305.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/18aaa1b87a36/pbio.1001305.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/23dad7d3d694/pbio.1001305.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/21072a795cd3/pbio.1001305.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fca/3323522/025a5d29ddd6/pbio.1001305.g007.jpg

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