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Cofactor engineering of intracellular CoA/acetyl-CoA and its subsequent effect on isoamyl acetate production in Escherichia coli.

机译：细胞内CoA /乙酰辅酶A的辅因子工程及其对大肠杆菌中乙酸异戊酯生产的后续影响。

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Traditional metabolic engineering focused on pathway manipulation strategies like amplification addition or deletion of pathway to manipulate fluxes. However, cofactors play an essential role in cellular metabolism and their manipulation has the potential to be used, as an additional tool to achieve desired metabolic engineering goals.; Coenzyme A and its derivative acetyl-CoA are important cofactors involved in many biosynthetic pathways and precursors for many industrially useful compounds. Our study focused on increasing the intracellular level/fluxes of CoA and acetyl-CoA. This was accomplished by overexpression of key rate controlling enzyme panK in the CoA biosynthesis pathway along with simultaneous supplementation of precursor pantothenic acid. The effect of such precise alteration of CoA metabolism on extracellular metabolite formation was studied. The utility of CoA manipulation system in enhancing production of isoamyl acetate, an industrially useful compound derived from acetyl-CoA was demonstrated.{09}This novel approach of cofactor manipulation was combined with the more traditional approach of competing pathway deletion, acetate production pathway in this case, to further enhance isoamyl acetate productivity.; Overexpression of panK led to a significant increase in CoA levels. Acetyl-CoA levels also increased but not as much as CoA leaving much of it in an unacetylated form. The central carbon flux was enhanced, either by overexpression of pdh or pps to increase acetyl-CoA, under elevated CoA levels. The flux through the acetyl-CoA node increased under such conditions. This enhanced carbon flux was efficiently channeled to isoamyl acetate production pathway by inactivating the acetate production pathway. The combination of these metabolic engineering strategies led to a significant increase in isoamyl acetate production.; We used production of isoamyl acetate as a model system to demonstrate the beneficial effects of CoA/acetyl-CoA manipulations in enhancing product productivity. This methodology can be easily extended to any other production systems involving the cofactors CoA/acetyl-CoA. Additional studies in our lab have shown that CoA/acetyl-CoA manipulation system is useful in improving productivities of succinate and lycopene.
机译：传统的代谢工程学专注于途径操纵策略，例如扩增，增加或删除途径以操纵通量。然而，辅因子在细胞代谢中起着至关重要的作用，它们的操纵有可能被用作实现理想的代谢工程目标的附加工具。辅酶A及其衍生物乙酰辅酶A是重要的辅因子，涉及许多生物合成途径和许多工业上有用的化合物的前体。我们的研究集中于增加CoA和乙酰辅酶A的细胞内水平/通量。这是通过在CoA生物合成途径中过表达关键速率控制酶panK以及同时补充前体泛酸来实现的。研究了CoA代谢的这种精确变化对细胞外代谢物形成的影响。证明了CoA操纵系统在提高乙酸异戊酯（一种从乙酰基CoA衍生而来的工业上有用的化合物）的生产中的效用。{09}将这种新型的辅因子操纵方法与竞争途径缺失的更传统方法相结合，即乙酸酯酶生产途径。在这种情况下，进一步提高了乙酸异戊酯的生产率。 panK的过表达导致CoA水平显着增加。乙酰辅酶A水平也有所增加，但增幅不及辅酶A，因此大部分以未乙酰化形式存在。在升高的CoA水平下，通过过度表达pdh或pps来增加乙酰基CoA，可以提高中心碳通量。在这种条件下，通过乙酰基-CoA节点的通量增加。通过灭活乙酸酯生产途径，这种增强的碳通量被有效地引导至乙酸异戊酯生产途径。这些代谢工程策略的组合导致乙酸异戊酯的产量显着增加。我们使用乙酸异戊酯的生产作为模型系统来证明CoA /乙酰辅酶A操纵对提高产品生产率的有益作用。该方法可以轻松扩展到涉及辅因子CoA /乙酰辅酶A的任何其他生产系统。我们实验室的其他研究表明，CoA /乙酰辅酶A操纵系统可用于提高琥珀酸酯和番茄红素的生产率。

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