A mechanochemical switch to control radical intermediates.
B₁₂-dependent enzymes employ radical species with exceptional prowess to catalyze some of the most chemically challenging, thermodynamically unfavorable reactions. However, dealing with highly reactive intermediates is an extremely demanding task, requiring sophisticated control strategies to prevent unwanted side reactions. Using hybrid quantum mechanical/molecular mechanical simulations, we follow the full catalytic cycle of an AdoB₁₂-dependent enzyme and present the details of a mechanism that utilizes a highly effective mechanochemical switch. When the switch is "off", the 5'-deoxyadenosyl radical moiety is stabilized by releasing the internal strain of an enzyme-imposed conformation. Turning the switch "on," the enzyme environment becomes the driving force to impose a distinct conformation of the 5'-deoxyadenosyl radical to avoid deleterious radical transfer. This mechanochemical switch illustrates the elaborate way in which enzymes attain selectivity of extremely chemically challenging reactions.
Laboratory of Computational Chemistry and Biochemistry, EPFL , Lausanne, Switzerland 1015.
Elizabeth
E
Brunk
Whitney F
WF
Kellett
Nigel G J
NG
Richards
Ursula
U
Rothlisberger
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055162:Biocatalysis; D001696:Biomechanical Phenomena; D055598:Chemical Phenomena; D003038:Cobamides / Q000737:chemistry / Q000378:metabolism*; D030562:Databases, Protein; D005609:Free Radicals / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D006865:Hydrogenation; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D008765:Methylmalonyl-CoA Mutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011424:Propionibacterium / Q000201:enzymology; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000214:Acyl Coenzyme A; D001426:Bacterial Proteins; D003038:Cobamides; D005609:Free Radicals; D021122:Protein Subunits; D011994:Recombinant Proteins; C015357:methylmalonyl-coenzyme A; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide