A terpene synthase-cytochrome P450 cluster in Dictyostelium discoideum produces a novel trisnorsesquiterpene
- University of Tennessee, United States
- Max Planck Institute for Chemical Ecology, Germany
- University of Bonn, Germany
- Baylor College of Medicine, United States
- University of Tennessee Health Science Center, United States
Abstract
Terpenoids are enormously diverse, but our knowledge of their biosynthesis and functions is limited. Here we report on a terpene synthase (DdTPS8)-cytochrome P450 (CYP521A1) gene cluster that produces a novel C12 trisnorsesquiterpene and affects the development of Dictyostelium discoideum. DdTPS8 catalyzes the formation of a sesquiterpene discoidol, which is undetectable from the volatile bouquet of wild type D. discoideum. Interestingly, a DdTPS8 knockout mutant lacks not only discoidol, but also a putative trisnorsesquiterpene. This compound was hypothesized to be derived from discoidol via cytochrome P450 (CYP)-catalyzed oxidative cleavage. CYP521A1, which is clustered with DdTPS8, was identified as a top candidate. Biochemical assays demonstrated that CYP521A1 catalyzes the conversion of discoidol to a novel trisnorsesquiterpene named discodiene. The DdTPS8 knockout mutant exhibited slow progression in development. This study points to the untapped diversity of natural products made by D. discoideum, which may have diverse roles in its development and chemical ecology.
Data availability
The sequence for CYP521A1 has been deposited in the GenBank database (accession nos. MH923436).
Article and author information
Author details
Funding
University of Tennessee Institute of Agriculture
- Feng Chen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Merijn R Kant, University of Amsterdam, Netherlands
Version history
- Received: December 12, 2018
- Accepted: May 3, 2019
- Accepted Manuscript published: May 7, 2019 (version 1)
- Version of Record published: May 17, 2019 (version 2)
Copyright
© 2019, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A terpene synthase-cytochrome P450 cluster in Dictyostelium discoideum produces a novel trisnorsesquiterpene
eLife 8:e44352.
https://doi.org/10.7554/eLife.44352
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The ATPase p97 (also known as VCP, Cdc48) has crucial functions in a variety of important cellular processes such as protein quality control, organellar homeostasis, and DNA damage repair, and its de-regulation is linked to neuromuscular diseases and cancer. p97 is tightly controlled by numerous regulatory cofactors, but the full range and function of the p97–cofactor network is unknown. Here, we identify the hitherto uncharacterized FAM104 proteins as a conserved family of p97 interactors. The two human family members VCP nuclear cofactor family member 1 and 2 (VCF1/2) bind p97 directly via a novel, alpha-helical motif and associate with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells. VCF1/2 localize to the nucleus and promote the nuclear import of p97. Loss of VCF1/2 results in reduced nuclear p97 levels, slow growth, and hypersensitivity to chemical inhibition of p97 in the absence and presence of DNA damage, suggesting that FAM104 proteins are critical regulators of nuclear p97 functions.
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Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years old) and centenarians.
Methods: The study included 812 (women: 84.4%) for centenarians and 1,498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole genome sequencing or DNA microarray-imputation methods. LASSO and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression.
Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p = 2.21 × 10-22) and ADIPOQ (p = 5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI.
Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old.
Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program 'Tonomachi Research Complex' Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.
