Systematic enzyme engineering for clean haprin industry

【Author】

Xin-Hui Xing;Nan Su;Chong Zhang;

【Abstract】

Heparin,a highly sulfated,acidic,linear and complex polysaccharide belonging to the family of heparin/heparan sulfate glycosaminglycans,is a polydisperse mixture with a molecular weight ranging from 5,000 to 40,000 Da and an average molecular weight of 12,000-15,000 Da.Heparin was discovered by McLean and Howell in 1916 and first used for clinical trials as anticoagulant drugs in 1935.Now heparin is mainly separated from pig intestine mucosa and further purified for the pharmaceutical use.Although heprain has been wildly used for cardiovascular surgery and the prevention of venous thromboembolism,some undesirable side effects including hemorrhagic complications and heparin-induced thrombocytopenia(HIT)have limited its application.Low molecular weight heparins(LMWHs),with a molecular weight of approximately 3,000-8,000 Da and an average molecular weight of approximately 5,000 Da,exhibit anticoagulant activity similar to heparin but lower risk in bleeding complications and HIT compared with heparin.LMWHs are thus gradually replacing heparin in clinical applications.Furthermore,LMWHs are also used for patients with pulmonary embolism due to its subcutaneously bioavailability,more predictable pharmacodynamics and longer half-lives.For developing the green,effective and safe bioprocess to purify the raw material of heparin and produce the LMWHs,enzyme technology is a promising way.However,the low productivity and high cost of the enzymes pertaining to heparin industry hinder the technological progress.For solving these problems,we systematically developed a platform for design of the fusion enzymes to produce the heparinases and chondroitinases,and successfully established the enzymatic processes for heparin purification and LMWHs production as well construction of LMWHs library for new non-anticoagulant drug discovery.

【Keywords】

Chondroitinases;;Enzymatic Engineering;;Fusion protein,Heparinase;;Heparin;;Low molecular weight heparins

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