The shikimate pathway is a necessary pathway for the synthesis of aromatic compounds. The intermediate products of the shikimate pathway and its branching pathway have promising properties in many fields, especially in the pharmaceutical industry. Many important compounds, such as shikimic acid, quinic acid, chlorogenic acid, gallic acid, pyrogallol, catechol and so on, can be synthesized by the shikimate pathway. Among them, shikimic acid is the key raw material for the synthesis of GS4104 (Tamiflu^®), an inhibitor of neuraminidase against avian influenza virus. Quininic acid is an important intermediate for synthesis of a variety of raw chemical materials and drugs. Gallic acid and catechol receive widespread attention as pharmaceutical intermediates. It is one of the hotspots to accumulate many kinds of target products by rationally modifying the shikimate pathway and its branches in recombinant strains by means of metabolic engineering. This review considers the effects of classical metabolic engineering methods, such as central carbon metabolism (CCM) pathway modification, key enzyme gene modification, blocking the downstream pathway on the shikimate pathway, as well as several expansion pathways and metabolic engineering strategies of the shikimate pathway, and expounds the synthetic biology in recent years in the application of the shikimate pathway and the future development direction.

Pyruvate is a hub of various endogenous metabolic pathways, including glycolysis, TCA cycle, amino acid, and fatty acid biosynthesis. It has also been used as a precursor for pyruvate-derived compounds such as acetoin, 2,3-butanediol (2,3-BD), butanol, butyrate, and L-alanine biosynthesis. Pyruvate and derivatives are widely utilized in food, pharmaceuticals, pesticides, feed additives, and bioenergy industries. However, compounds such as pyruvate, acetoin, and butanol are often chemically synthesized from fossil feedstocks, resulting in declining fossil fuels and increasing environmental pollution. Metabolic engineering is a powerful tool for producing eco-friendly chemicals from renewable biomass resources through microbial fermentation. Here, we review and systematically summarize recent advances in the biosynthesis pathways, regulatory mechanisms, and metabolic engineering strategies for pyruvate and derivatives. Furthermore, the establishment of sustainable industrial synthesis platforms based on alternative substrates and new tools to produce these compounds is elaborated. Finally, we discuss the potential difficulties in the current metabolic engineering of pyruvate and derivatives and promising strategies for constructing efficient producers.

Co-production of polyhydroxyalkanoate (PHA) and amino acids makes bacteria effective microbial cell factories by secreting amino acids outside while accumulating PHA granules inside. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) is one of the PHAs with biocompatibility and fine mechanical properties, but its production is limited by the low level of intracellular propionyl-CoA. l-Isoleucine producing Corynebacterium glutamicum strain WM001 were analyzed by genome and transcriptome sequencing. The results showed that the most over-expressed genes in WM001 are relevant not only to l-isoleucine production but also to propionyl-CoA accumulation. Compared to the wild-type C. glutamicum ATCC13869, the transcriptional levels of the genes prpC2, prpD2, and prpB2, which are key genes relevant to propionyl-CoA accumulation, increased 26.7, 25.8, and 28.4-folds in WM001, respectively; and the intracellular level of propionyl-CoA increased 16.9-fold in WM001. When the gene cluster phaCAB for PHA biosynthesis was introduced into WM001, the recombinant strain WM001/pDXW-8-phaCAB produced 15.0 g/L PHBV with high percentage of 3-hydroxyvalerate as well as 29.8 g/L l-isoleucine after fed-batch fermentation. The maximum 3-hydroxyvalerate fraction in PHBV produced by WM001/pDXW-8-phaCAB using glucose as the sole carbon source could reach 72.5%, which is the highest reported so far. Genome and transcriptome analysis showed that C. glutamicum WM001 has potential to accumulate l-isoleucine and propionyl-CoA pool. This was experimentally confirmed by introducing the phaCAB gene cluster into WM001. The recombinant strain WM001/pDXW-8-phaCAB produced high levels of PHBV with high 3-hydroxyvalerate fraction as well as l-isoleucine. Because of its high level of intracellular propionyl-CoA pool, WM001 might be used for producing other propionyl-CoA derivatives.

The phosphoenol pyruvate–oxaloacetate–pyruvate-derived amino acids (POP-AAs) comprise native intermediates in cellular metabolism, within which the phosphoenol pyruvate–oxaloacetate–pyruvate (POP) node is the switch point among the major metabolic pathways existing in most living organisms. POP-AAs have widespread applications in the nutrition, food, and pharmaceutical industries. These amino acids have been predominantly produced in Escherichia coli and Corynebacterium glutamicum through microbial fermentation. With the rapid increase in market requirements, along with the global food shortage situation, the industrial production capacity of these two bacteria has encountered two bottlenecks: low product conversion efficiency and high cost of raw materials. Aiming to push forward the update and upgrade of engineered strains with higher yield and productivity, this paper presents a comprehensive summarization of the fundamental strategy of metabolic engineering techniques around phosphoenol pyruvate–oxaloacetate–pyruvate node for POP-AA production, including L-tryptophan, L-tyrosine, L-phenylalanine, L-valine, L-lysine, L-threonine, and L-isoleucine. Novel heterologous routes and regulation methods regarding the carbon flux redistribution in the POP node and the formation of amino acids should be taken into consideration to improve POP-AA production to approach maximum theoretical values. Furthermore, an outlook for future strategies of low-cost feedstock and energy utilization for developing amino acid overproducers is proposed.