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A Highly Convergent Synthesis of Myristoyl‐carba(dethia)‐coenzyme A
Author(s) -
Tautz Lutz,
Rétey Janos
Publication year - 2010
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200901410
Subject(s) - myristoylation , chemistry , stereochemistry , coenzyme a , cofactor , enzyme , rational design , chemical synthesis , adenosylcobalamin , active site , biochemistry , in vitro , membrane , reductase , nanotechnology , materials science
Co‐translational myristoylation of the N‐terminal glycine residues of diverse signalling proteins is required for membrane attachment and proper function of these molecules. The transfer of myristate from myristoyl‐coenzyme A (myr‐CoA) is catalysed by the enzyme N ‐myristoyltransferase (Nmt). Nmt has been implicated in a number of human diseases, including cancer and epilepsy, as well as in pathogenic mechanisms such as fungal and virus infections, including HIV and hepatitis B. Rational design has led to the development of potent competitive inhibitors, including several non‐hydrolysable acyl‐CoA substrate analogues. Linear synthetic strategies, following the route of the original CoA synthesis, however, generate such analogues in very low overall yields that typically are not sufficient for in vivo studies. Herewe present a new, highly convergent synthesis of myristoyl‐carba(dethia)‐coenzyme A ( 1 ) that allows this substrate analogue to be obtained in a yield 11 times higher than that of the reported linear synthesis. In addition, enzymatic cleavage of the adenosine‐2′,3′‐cyclophosphate in the last step of the synthesis proved to be an efficient way to obtain the isomerically pure 3′‐phosphate 1 free of the 2′‐phosphate 13 .