Preface

Vitamin K is a fat-soluble vitamin with a 1,4-naphthoquinone structure bearing various side-chain moieties that is responsible for blood coagulation and bone homeostasis. It acts as the cofactor of γ-glutamyl carboxylase, which catalyzes the γ-carboxylation of glutamate residue of vitamin K-dependent proteins, including factors II (prothrombin), VII, IX, and X. The proteins that have γ-carboxylated glutamate residue are also found in the bone matrix and aortic vessel wall and are involved in the regulation of these structures' calcification.

In the past two decades, novel biological activities of vitamin K other than the coenzyme function of γ-glutamyl carboxylase have been reported. For example, vitamin K shows an anti-inflammatory effect via the inhibition of the NF-κB pathway, and steroidogenesis by the activation of cAMP-dependent protein kinase. In the vitamin K family, menaquinone-4 (MK-4) plays important roles in many biological systems, including enhancement of testosterone production and inhibition of arteriosclerosis and tumor progression. Further, MK-4 was identified as the specific ligand for the steroid and xenobiotic receptor (SXR) and it modulates the transcription of genes in osteoblast, hepatocyte, and intestinal cells. These novel functions of vitamin K could prevent and control exacerbations in non-communicable diseases and might contribute to prolonged life expectancy.

Ingested vitamin K from plants, animals, and fermented products is endogenously converted into MK-4. UbiA prenyltransferase domain-containing protein 1 (UBIAD1) was identified as a key enzyme for biosynthesis of MK-4. An unknown factor cleaves the side chain of vitamin K and generates 2-methyl-1,4-naphthoquinone (vitamin K3, menadione). UBIAD1 catalyzes MK-4 production from menadione and geranylgeranyl diphosphate derived from the mevalonate pathway. In organs of animals, including humans, MK-4 is the predominant form of vitamin K. These findings on non-classical activities of vitamin K indicate the existence of unrevealed mechanisms of action for physiological and pharmacological functions of vitamin K. In the case of vitamins A and D, the identification of active metabolites (retinoic acid for vitamin A, and 1α, 25-dihydroxyvitamin D3 for vitamin D) and the target nuclear receptors caused dramatic improvement in elucidation of their hormonal functions and clinical applications, while the metabolic pathway of vitamin K and properties of metabolites, including the possible unidentified active metabolites, remains unclear.

Vitamin K is an attractive lead compound for drug discovery. Several vitamin K derivatives have been synthesized, including possible metabolites, most of them consisting of structural features like those of natural vitamin K. Development of novel vitamin K derivatives with unique chemical structure and biological profile, especially those that elicit non-classical vitamin K functions, would lead to novel clinical applications of vitamin K.

This book discusses the biology and chemistry of vitamin K, which is helpful for fundamental and clinical investigations. I would like to sincerely thank all the authors who contributed to this book.

## **Hitoshi Shirakawa, Ph.D.**

Professor, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

## **Hiroyuki Kagechika, Ph.D.**

Professor, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan

## **Chapter 1**
