QM/MM Study of Human Transketolase: Thiamine Diphosphate Activation Mechanism and Complete Catalytic Cycle

A computational
model for human transketolase was proposed, showing
that thiamine diphosphate activation was based on His110 in place
of His481 reported in yeast transketolase. In addition, a complete
catalytic reaction pathway was investigated using d-xylulose-5-phosphate
and d-ribose-5-phosphate as substrates, showing at every
step a perfect superimposition of our model with high-resolution crystallographic
structures 3MOS, 4KXV, and 4KXX. This study shows that H2N4′
of the active thiamine diphosphate “V form” no longer
has a self-activating role but allows self-stabilization of the cofactor
and of the Breslow intermediate. These advances in our knowledge of
the human transketolase mechanism offer interesting prospects for
the design of new drugs, this enzyme being involved in several diseases,
and for a better understanding of the reactions catalyzed by transketolases
from other sources.