Recent Advances in Heterologous Synthesis Paving Way for Future Green-Modular Bioindustries: A Review With Special Reference to Isoflavonoids

Abstract

Isoflavonoids are well-known plant secondary metabolites that have gained importance in recent time due to their multiple nutraceutical and pharmaceutical applications. In plants, isoflavonoids play a role in plant defense and can confer the host plant a competitive advantage to survive and flourish under environmental challenges. In animals, isoflavonoids have been found to interact with multiple signaling pathways and have demonstrated estrogenic, antioxidant and anti-oncologic activities in vivo. The activity of isoflavonoids in the estrogen pathways is such that the class has also been collectively called phytoestrogens. Over 2,400 isoflavonoids, predominantly from legumes, have been identified so far. The biosynthetic pathways of several key isoflavonoids have been established, and the genes and regulatory components involved in the biosynthesis have been characterized. The biosynthesis and accumulation of isoflavonoids in plants are regulated by multiple complex environmental and genetic factors and interactions. Due to this complexity of secondary metabolism regulation, the export and engineering of isoflavonoid biosynthetic pathways into non-endogenous plants are difficult, and instead, the microorganisms Saccharomyces cerevisiae and Escherichia coli have been adapted and engineered for heterologous isoflavonoid synthesis. However, the current ex-planta production approaches have been limited due to slow enzyme kinetics and traditionally laborious genetic engineering methods and require further optimization and development to address the required titers, reaction rates and yield for commercial application. With recent progress in metabolic engineering and the availability of advanced synthetic biology tools, it is envisaged that highly efficient heterologous hosts will soon be engineered to fulfill the growing market demand.

Comparative Study of Natural Antioxidants from Glycine max, Anethum graveolensand Pimpinella anisum Seed and Sprout Extracts Obtained by Ultrasound-Assisted Extraction

“…Isoflavones are considered the most estrogenic compounds [74] and the most representative among this class are daidzein, genistein, biochanin A, formononetin and glycitein [75]. Findings have shown that traditional herbal formulations have positive effects in ameliorating menopausal symptoms and improving the quality of sleep and also the quality of life [76]. The phytoestrogens daidzein and genistein, having a structural resemblance to 17-β-estradiol, can protect against a lot of illnesses, including various forms of breast, prostate or bowel cancer, cardiovascular diseases, and osteoporosis and can relieve menopausal symptoms, as illustrated in Figure 4 [11,[77][78][79].…”

De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories

“…The current production of isoflavonoids relies on direct plant extraction. However, the low phytochemical abundance, significant investment of time, energy, and capital, and huge requirement for potentially toxic solvents have excluded this approach from being used as it is neither economical nor environmental-friendly 5 , 6 . Moreover, the cultivation of legumes is geographically uneven and the amounts of isoflavonoids vary greatly from cultivars and climatic conditions 7 .…”

Modular Engineering of Saccharomyces cerevisiae for De Novo Biosynthesis of Genistein

“…However, industrial production of genistein is facing prominent challenges due to the low abundance of legumes and the complex extraction process, inefficient chemical synthesis, and an environmentally unfriendly route [ 4 ]. Thus, the heterologous biosynthesis of isoflavonoids in microbes by synthetic biology offers great potential for the development of a green bioindustry [ 5 ].…”

“…Since S. cerevisiae is generally recognized as a safe (GRAS) organism, it has been employed to produce isoflavonoids [ 5 , 12 , 13 ]. By feeding precursor naringenin, the recombinant S. cerevisiae with heterologous expression of IFS produced genistein, and additional expression of plant CPR and HID could increase the production of genistein [ 14 , 15 ].…”