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Background  With a variety of physiological and pharmacological functions, menaquinone is an essential prenylated product that can be endogenously converted from phylloquinone (VK 1 ) or menadione (VK 3 ) via the expression of  Homo sapiens  UBIAD1 ( Hs UBIAD1). The methylotrophic yeast,  Pichia pastoris , is an attractive expression system that has been successfully applied to the efficient expression of heterologous proteins. However, the menaquinone biosynthetic pathway has not been discovered in  P. pastoris .    Results  Firstly, we constructed a novel synthetic pathway in  P. pastoris  for the production of menaquinone-4 (MK-4) via heterologous expression of  Hs UBIAD1. Then, the glyceraldehyde-3-phosphate dehydrogenase constitutive promoter (P  GAP  ) appeared to be mostsuitable for the expression of  Hs UBIAD1 for various reasons. By optimizing the expression conditions of  Hs UBIAD1, its yield increased by 4.37 times after incubation at pH 7.0 and 24 °C for 36 h, when compared with that under the initial conditions. We found  Hs UBIAD1 expressed in recombinant GGU-23 has the ability to catalyze the biosynthesis of MK-4 when using VK 1  and VK 3  as the isopentenyl acceptor. In addition, we constructed a ribosomal DNA (rDNA)-mediated multi-copy expression vector for the fusion expression of  Sa GGPPS and  Pp IDI, and the recombinant GGU-GrIG afforded higher MK-4 production, so that it was selected as the high-yield strain. Finally, the yield of MK-4 was maximized at 0.24 mg/g DCW by improving the GGPP supply when VK 3  was the isopentenyl acceptor.    Conclusions  In this study, we constructed a novel synthetic pathway in  P. pastoris  for the biosynthesis of the high value-added prenylated product MK-4 through heterologous expression of  Hs UBIAD1 and strengthened accumulation of GGPP. This approach could be further developed and accomplished for the biosynthesis of other prenylated products, which has great significance for theoretical research and industrial application.

Construction of a novel MK-4 biosynthetic pathway in Pichia pastoris through heterologous expression of HsUBIAD1