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Abstract Transient plant enzyme complexes formed via protein-protein interactions (PPIs) play crucial regulatory roles in secondary metabolism. Complexes assembled on cytochrome P450s (CYPs) are challenging to characterize metabolically due to difficulties in decoupling the PPIs’ metabolic impacts from the CYPs’ catalytic activities. Here, we developed a yeast-based synthetic biology approach to elucidate the metabolic roles of PPIs between a soybean-derived CYP, isoflavone synthase (GmIFS2), and other enzymes in isoflavonoid metabolism. By reconstructing multiple complex variants with an inactive GmIFS2 in yeast, we found that GmIFS2-mediated PPIs can regulate metabolic flux between two competing pathways producing deoxyisoflavonoids and isoflavonoids. Specifically, GmIFS2 can recruit chalcone synthase (GmCHS7) and chalcone reductase (GmCHR5) to enhance deoxyisoflavonoid production or GmCHS7 and chalcone isomerase (GmCHI1B1) to enhance isoflavonoid production. Additionally, we identified and characterized two novel isoflavoneO-methyltransferases interacting with GmIFS2. This study highlights the potential of yeast synthetic biology for characterizing CYP-mediated complexes.
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Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells
Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of well-studied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels.
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- Award ID(s):
- 2019074
- PAR ID:
- 10482745
- Editor(s):
- Dr. Barbara De Filippis, Dr. Alessandra
- Publisher / Repository:
- MDPI
- Date Published:
- Journal Name:
- Cancers
- Volume:
- 15
- Issue:
- 18
- ISSN:
- 2072-6694
- Page Range / eLocation ID:
- 4645
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/cancers15184645
