Discovery of the new enzyme, available for manufacturing of cis-4-Hydroxy-L-proline, a material of pharmaceutical and cosmetic products

Fri, May 13, 2011

Prof. Kuniki Kino (Department of Applied Chemistry, Faculty of Science and Engineering) and Dr. Ryotaro Hara (Research Institute for Science and Engineering) have discovered New Enzyme, which contributes establish an innovative new industrial manufacturing method for cis-4-hydroxy-L-proline, an amino acid derivative.

cis-4-Hydroxy-L-proline is a kind of amino acid which is hydroxylated in the 4-position of L-proline and it is believed to have potential as a raw material for pharmaceutical and cosmetic products. trans-4-Hydroxy-L-proline , a cis-4-hydroxy-L-proline stereoisomer , has been used for a broad range of applications since an efficient fermentation production method was established by KYOWA HAKKO BIO CO., LTD. in 1997. cis-4-Hydroxy-L-proline, however, could only be manufactured through a complex chemical synthetic procedure, and due to the high costs involved, usage has been limited.

Using a new enzyme that positionally and stereoscopically hydroxylates L-proline discovered by Prof. Kino and Dr. Hara, KYOWA HAKKO BIO has established an efficient industrial production method for cis-4-hydroxy-L-proline. As a result, they are now able to steadily supply highly pure cis-4-hydroxy-L-proline at a low cost. Further, they now have the technology to cheaply produce a variety of highly pure proline derivatives.

Waseda University, as a “Research University”, keeps contributing to the development of industry through promoting Research collaborations.

Research Collaboration and Promotion Center (WTLO)

1: The synthesis methods for inserting a hydroxyl group in a specified place within L-proline are extremely difficult. Previously, cis-4-hydroxy-L-proline was obtained through chemical synthesis by alteration of the position of the hydroxyl group of trans-4-hydroxy-L-proline which was obtained from extraction from biological materials or a fermentation technique.This method protects highly reactivity functional groups with a high cost reagent, and after inverting the hydroxyl it undergoes a deprotection step with many complicated procedural steps, which may reduce yield. KYOWA HAKKO BIO’s method is a highly profitable and low-cost method with low environmental impact that involves a one-step reaction using an enzyme injected directly into a hydroxyl group of low cost L-proline.

2: trans-4-Hydroxy-L-proline is an amino acid found in skin collagen and is known as a stabilizer of skin collagen. As it is known to stimulate collagen synthesis and retain moisture in the keratin layer it is widely used in cosmetics and health foods. However, cis-4-hydroxy-L-proline is its stereoisomer and although it is not a biogenic substance it is highly similar in structure so may have undiscovered pharmacological effects. Further, as some pharmaceutical products have a proline framework, the establishment of a system for its bulk supply at a low price is expected to lead to the spread of its use as a raw material in pharmaceutical product development.

3: Although their molecular formulae are the same, no matter how they are moved or rotated in three dimensions, the different isomers cannot be identical. As shown in Diagram 1, the only difference between trans-4-hydroxy-L-proline and cis-4-hydroxy-L-proline is the direction of linkage of the hydroxyl group and they are known as stereoisomers.

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