Discovery and development of direct thrombin inhibitors the binding site for the globular amino-terminal domain and exosite 1 is the binding site for the acidic carboxy-terminal domain of hirudin. Native hirudin, a 65-amino-acid polypeptide, is produced in the parapharyngeal glands of medicinal leeches. Hirudins today are produced by recombinant biotechnology using yeast. These recombinant hirudins lack a sulfate group at Tyr-63 and are therefore called desulfatohirudins. They have a 10-fold lower binding affinity to thrombin compared to native hirudin, but remain a highly specific inhibitor of thrombin and have an inhibition constant for thrombin in the picomolar range. Renal clearance and degradation account for the most part
DNA damage (naturally occurring) or via environmental factors. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage. Damage to DNA that occurs naturally can result from metabolic or hydrolytic processes. Metabolism releases compounds that damage DNA including reactive oxygen species, reactive nitrogen species, reactive carbonyl species, lipid peroxidation products and alkylating agents, among others, while hydrolysis cleaves chemical bonds in DNA. Naturally occurring oxidative DNA damages arise at least 10,000 times per cell per day in humans and 50,000 times or more per cell per day in rats,