Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 144, Issue 48, Pages 21843-21847Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c09626
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Funding
- SENS Research Foundation
- American Diabetes Association Pathway to Stop Diabetes Grant [1-17-VSN-04]
- National Institutes of Health Chemical Biology Training Grant [T32 GM067543]
- Yale University
- Amgen
- Dreyfus Foundation
- Sloan Foundation
- NSF CAREER [1653793]
- NIH [GM118614]
- National Science Foundation [CNS 08-21132]
- Roberts fellowship
- Dox fellowship
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1653793] Funding Source: National Science Foundation
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Pentosinane, a complex nonenzymatic post-translational modification of proteins, has been synthesized for the first time in this study. The results show that pentosinane is likely to be more abundant in vivo than previously appreciated. This finding represents a critical step towards understanding the role of pentosinane in human biology.
Pentosinane is a structurally complex nonenzymatic post-translational modification of proteins believed to be present in all living things. It falls into the category of advanced glycation end products (AGEs) and is structurally related to the other AGEs pentosidine and glucosepane. Although pentosidine and glucosepane have been widely studied for their role in wide-ranging conditions (e.g., diabetes mellitus, Alzheimer's disease, and human aging), relatively little is known about pentosinane. Interestingly, previous reports have suggested that pentosidine may derive from pentosinane. The (patho)physiological significance of pentosinane in humans is largely unexplored. As a first step to address this knowledge gap, we report herein the first total synthesis of pentosinane. Our synthesis is high yielding (1.7% over seven steps), concise, and enantioselective, and it leverages a strategy for synthesizing 2,5-diaminoimidazoles previously developed by our lab. Access to synthetic pentosinane has allowed us to perform additional studies showing that its oxidation to pentosidine is both pH and oxygen dependent and is substantially slower under physiological conditions than previously believed. Additionally, pentosinane rapidly decomposes under harshly acidic conditions typically employed for pentosidine isolation. Taken together, these results suggest that pentosinane is likely to be more abundant in vivo than previously appreciated. We believe these results represent a critical step toward illuminating the role(s) of pentosinane in human biology.
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