Sawant Neha, Chandra Sudeshna, Appukuttan Deepti, Singh Harinder
Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS Deemed to be University, Vile Parle (West), Mumbai, 400056, India.
Hanse-Wissenschaftskolleg - Institute for Advanced Study (HWK), Delmenhorst, Lower Saxony, Germany.
Mol Biol Rep. 2025 Jan 31;52(1):182. doi: 10.1007/s11033-025-10308-6.
Since the 1990s, fatty acids (FA) have drawn significant industrial attention due to their diverse applications creating a demand for biological systems capable of producing high FA titers. While various strategies have been explored to achieve this, many of the conventional approaches rely on extensive genetic manipulations, which often result in strain instability, thus limiting its potential to yield better FA titers. Moreover, stresses such as pH, osmotic, and oxidative imbalances generated during FA production aggravate these challenges, further limiting FA titers. Under stress conditions, the cellular system responds by regulating stress-response proteins to bring about homeostasis. Recent findings suggest that transmembrane proteins, regulators of two-component systems, and cytoplasmic regulators can be strategically leveraged to address the problems related to stress-induced strain instability. Thus, non-conventional genetic targets, like chaperones (e.g., heat shock proteins) and DNA-binding transcriptional regulators (e.g., RcdA), which are not directly involved in FA metabolism, represent promising candidates to enhance strain stability and FA yields. Tools like Opt-Box and Weighted Gene Co-expression Network Analysis (WGCNA) serve as excellent platforms for understanding the cross-talk between these regulators and downstream enzymes. This review emphasizes the need for a shift towards identifying novel genetic targets by employing advanced in silico analysis and explains several molecular techniques that can aid in strain construction. Lastly, it discusses certain non-conventional gene targets that can help to overcome strain instability arising due to various stresses generated during/due to FA production.
自20世纪90年代以来，脂肪酸（FA）因其多样的应用而受到了工业界的广泛关注，这催生了对能够产生高脂肪酸滴度的生物系统的需求。虽然人们已经探索了各种策略来实现这一目标，但许多传统方法依赖于广泛的基因操作，这往往导致菌株不稳定，从而限制了其产生更高脂肪酸滴度的潜力。此外，在脂肪酸生产过程中产生的诸如pH值、渗透压和氧化失衡等压力加剧了这些挑战，进一步限制了脂肪酸滴度。在压力条件下，细胞系统通过调节应激反应蛋白来实现内稳态。最近的研究结果表明，可以战略性地利用跨膜蛋白、双组分系统的调节因子和细胞质调节因子来解决与应激诱导的菌株不稳定相关的问题。因此，诸如伴侣蛋白（如热休克蛋白）和DNA结合转录调节因子（如RcdA）等不直接参与脂肪酸代谢的非常规遗传靶点，是提高菌株稳定性和脂肪酸产量的有希望的候选者。Opt-Box和加权基因共表达网络分析（WGCNA）等工具是理解这些调节因子与下游酶之间相互作用的优秀平台。本综述强调了通过采用先进的计算机分析转向识别新的遗传靶点的必要性，并解释了几种有助于菌株构建的分子技术。最后，它讨论了某些非常规基因靶点，这些靶点有助于克服由于脂肪酸生产过程中产生的各种压力/或由于脂肪酸生产而导致的菌株不稳定。
