Fysikum, Stockholms Universitet
Physics department, Stockholm University
Quantum Chemistry group
Katarina Roos
PhD student
Kvantkemi FK7009
Fysikums räknestuga
Proteins with a novel manganese-iron center have recently been found in the pathogens Chlamydia trachomatis and Mycobacterium tuberculosis. B3LYP hybrid density functional theory is used to study the function of these proteins.
Ribonucleotide reductase (RNR) catalyses the reduction of ribonucleotides to deoxyribonucleotides, the building blocks for DNA synthesis. An oxygen-cleaving reaction at a diiron center leads to the formation of a stable tyrosyl radical needed for catalysis. Class Ic R2 from Chlamydia trachomatis (Ct) lacks the radical bearing tyrosine that is crucial for activity in conventional class I RNR. Instead of the Fe(III)Fe(III)Tyr(rad) active state, Ct RNR has Mn(IV)Fe(III) at the metal center of R2. An explanation is proposed for why the enzyme needs this novel metal center (K. Roos and P.E.M. Siegbahn, Biochemistry, 48, 1878-1887 (2009)).
Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis, a disease with 1.7 million deaths yearly. Rv0233 is one of the ten most upregulated proteins in the virulent strain compared to the avirulent vaccine strain. The active site of Rv0233 has a mixed manganese-iron center with a binding motif identical to that of RNR from Chlamydia trachomatis. The function of Rv2033 is unknown, but the protein is thought to be involved in lipid metabolism.
In the vicinity of the metal center an unprecedented tyrosine-valine crosslink is observed. The function of the link could be to force the substrate to be in a correct position for catalysis, and the prescence of the link might therefore be crucial for the protein function. A possible reaction mechanism of the formation of this novel cross link is proposed.
Department of Physics
Arrhenius Laboratories C463
Stockholm University
S - 106 91 Stockholm