Compound K Production: Achievements and Perspectives

Abstract

Compound K (CK) is one of the major metabolites found in mammalian blood and organs following oral administration of Panax plants. CK, also known as minor ginsenoside, can be absorbed in the systemic circulation. It has garnered significant attention in healthcare and medical products due to its pharmacological activities, such as antioxidation, anticancer, antiproliferation, antidiabetics, neuroprotection, and anti-atherogenic activities. However, CK is not found in natural ginseng plants but in traditional chemical synthesis, which uses toxic solvents and leads to environmental pollution during the harvest process. Moreover, enzymatic reactions are impractical for industrial CK production due to low yield and high costs. Although CK could be generated from major ginsenosides, most ginsenosides, including protopanaxatriol-oleanane and ocotillol-type, are not converted into CK by catalyzing β-glucosidase. Therefore, microbial cell systems have been used as a promising solution, providing a safe and efficient approach to CK production. This review provides a summary of various approaches for the production of CK, including chemical and enzymatic reactions, biotransformation by the human intestinal bacteria and endophytes as well as engineered microbes. Moreover, the approaches for CK production have been discussed to improve the productivity of target compounds.

Keywords: Compound K (CK); Panax ginseng; Saccharomyces cerevisiae; endophytes; β-glucosidase.

Figure 1

The chemical structure of CK and its biological activities.

Figure 2

The functional mechanism of CK on different cancer cell lines. Abbriviation: AMPK, adenosine monophosphate protein kinase; Akt, protein kinase B; GSK3β, glycogen synthase kinase; HIF, hypoxia inducible factor; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MAPK, mitogen-activated protein kinase; MMP, metalloproteinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription.

Figure 3

Biotransformation pathway for CK production by enzymatic reaction and microbes.

Figure 4

The proposed biosynthetic pathway for CK production in engineered yeasts. Blue: yeast native enzymes; purple: P. ginseng enzymes, and green: A. thaliana enzyme. Intermediates: HMG-CoA, β-Hydroxy β-methylglutaryl-CoA; DMAPP, dimethylallyl pyrophosphate; IPP, isopentenyl pyrophosphate; FPP, farnesyl diphosphate; MVA, mevalonate; MVAP, mevalonate 5-phosphate; MVAPP, mevalonate 5-pyrophosphate; UTP, uridine triphosphate; UDP, uridine diphosphate; and UMP, uridine monophosphate. Enzymes: ACS: acetyl-CoA synthase; ADH2, alcohol dehydrogenase; HK, hexokinase; ALD6, acetaldehyde dehydrogenase; ERG10, acetyl-CoA C-acetyltransferase; ERG13, HMG-CoA synthase; HMG, 3-hydroxy-3-methylglutaryl-CoA reductase; ERG12, mevalonate kinase; ERG8, phosphomevalonate kinase; ERG19, diphosphomevalonate; IDI, isopentenyl diphosphate-isomerase; ERG20, farnesyl diphosphate synthase; ERG9, squalene synthase; ERG1, squalene epoxidase; ERG7, lansterol synthase; CPR, cytochrome P450 reductase; PPDS, protopanaxadiol synthase; UGT, UDP-glycosyltransferase; PGM: phosphoglucomutase 2; FKS1, 1,3-β-D-glucan synthase; GLC3, glycogen-branching enzyme; and ALG5, glycosyltransferase on N-linked glycosylation.