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May 12, 2011

Kyowa Hakko Bio announces the commencement of
commercial production of cis-4-Hydroxy-L-proline

Tokyo, May 12, 2011---Kyowa Hakko Bio Co., Ltd. ("Kyowa Hakko Bio") announced today that it has established an innovative new industrial manufacturing method for cis-4-hydroxy-L-proline, an amino acid derivative. Commercial production is scheduled to commence in the first half of 2011.

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 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 Professor Dr. Kuniki Kino of Waseda University, Kyowa Hakko Bio has established an efficient industrial production method for cis-4-hydroxy-L-proline. As a result, we are now able to steadily supply highly pure cis-4-hydroxy-L-proline at a low cost. Further, we now have the technology to cheaply produce a variety of highly pure proline derivatives such as D-proline and cis-3-hydroxy-L-proline, in addition to trans-4-hydroxy-L-proline. With the addition of cis-4-hydroxy-L-proline to our line up, we will be better able to meet the diverse needs of our customers.

About an innovative new industrial manufacturing method for cis-4-hydroxy-L-proline
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.
About an innovative new industrial manufacturing method for cis-4-hydroxy-L-proline

About trans-4-Hydroxy-L-proline
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.

About stereoisomer
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.

About Kyowa Hakko Bio
Kyowa Hakko Bio, was the first in the world to achieve industrial production of amino acids using fermentation methods, leverages its advanced fermentation technologies to advance life science and aims to manufacture and supply useful compounds through fermentation and to contribute to the health and wellbeing of people around the world.



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