New aspects of microbial vitamin K2 production by expanding the product spectrum

Zimeng Zhang,Yumei Sun,Linxia Liu,Dawei Zhang,Chuan Liu

doi:10.1186/s12934-021-01574-7

Abstract

Vitamin K2 (menaquinone, MK) is an essential lipid-soluble vitamin with critical roles in blood coagulation and bone metabolism. Chemically, the term vitamin K2 encompasses a group of small molecules that contain a common naphthoquinone head group and a polyisoprenyl side chain of variable length. Among them, menaquinone-7 (MK-7) is the most potent form. Here, the biosynthetic pathways of vitamin K2 and different types of MK produced by microorganisms are briefly introduced. Further, we provide a new aspect of MK-7 production, which shares a common naphthoquinone ring and polyisoprene biosynthesis pathway, by analyzing strategies for expanding the product spectrum. We review the findings of metabolic engineering strategies targeting the shikimate pathway, polyisoprene pathway, and menaquinone pathway, as well as membrane engineering, which provide comprehensive insights for enhancing the yield of MK-7. Finally, the current limitations and perspectives of microbial menaquinone production are also discussed. This article provides in-depth information on metabolic engineering strategies for vitamin K2 production by expanding the product spectrum.

Highlights

Based on the side-chain structure, vitamin K isoforms are categorized as vitamin K1, vitamin K2 and vitamin K3 (Fig. 1) [13–15]
Yang et al [63] overexpressed each of the above cistrons using strong promoters in B. subtilis 168, and the results revealed that only the step reaction by membrane-bound enzymes polyprenyltransferase (MenA), i.e. the prenylation of DHNA to DMK was a rate-limiting step in the MK-7 pathway
Traditionally, vitamin K is known for its essential role in the blood coagulation cascade and it is involved in the maintenance of bone, preventing arterial hardening, modulating inflammation, and neuroprotection [9, 92]

Summary

Introduction

Dr Henrik Dam discovered vitamin K in the 1930s and shared the 1943 Nobel Prize in medicine with Edward Doisy for their work on this fat-soluble bioactive compound [1–3]. Vitamin K serves as a cofactor for γ-glutamyl carboxylase (GGCX), which converts glutamic acid residues of vitamin K-dependent proteins (VKDPs) into γ-carboxyglutamic acid (Gla). There are more than 15 types of VKDPs, including coagulation factors II (prothrombin), VII, IX, and X, as well as the anticoagulation factors C, protein S, and osteocalcin [4–7]. The term vitamin K denotes a series of fat-soluble compounds that contain a 2-methyl-1,4-naphthoqumone moiety as the basic skeleton and an isoprenoid chain at the 3-position [12]. Vitamin K2 contains an unsaturated aliphatic side chain with a variable number (n) of 4 to 13 isoprene units and is referred to as MK-n [17]. Vitamin K1 is currently produced via chemical synthesis, and there is little evidence

Objectives

Findings

Conclusion