Diradicals Identified for the First Time in Sugars Interconversion

Maintaining a homeostatic blood-sugar level in body is important, because the imbanlaced blood-sugar level is unhealthy. The homeostasis, however, is dependent on the gross metabolism of sugars in our body. Scientists are therefore keen to sort out how the sce-nario is precisely implemented at both the microscorpic and macroscopric levels.

Pentose, a 5-carbon sugar, stands at the conflux of the sugar metabolic network, where the pentose phosphate pathway (also called PPP) is literally the playground where inter-conversion amid various types of sugars takes place.

Transketolase (TK) happens to be one of the enzymes in PPP, which facilitates the in-terconersion of sugars. TK is a thiamine diphosphate (ThDP)-dependent enzyme. ThDP, an active form of vitamin B1, is an organic “cofactor”, takes part in numerous essential biochemical reactions in living organisms.

When pentoses meet with TK, some magic happens: two pentoses can rearrange to form one fructose (a hexose, 6-carbon sugar) and one erythrose (a 4-carbon sugar) or, vice versa. That is, different types of sugars can be formed through such a reorganization process to meet our body’s needs.


Professor Tsung-Lin Li and his group have been dedicated to crack down this magical trick for a long period of time. TK transforms one sugar to the other, where ThDP ap-parently is the pivot that indeed directs the intricate enzyme-cofactor-substrate tango dance.

The ThDP-assisted keto-transferring reaction is chemically similar to the N-heterocyclic carbene-catalyzed benzoin condensation reaction, where a reactive carbene acts as the nucleophile converting an electrophilic canbonyl group to a nucleophilic form to allow condensation with the carbonyl group of a second molecule.

By taking advantage of the state-of-the-art X-ray beam source at Taiwan Photon Source (TPS), the team was able to determine liganded crystal structures of TK at ultrahigh resolution of 0.85 Å. Under this context the team is entitlted to take a sneak peek at the reaction center, thereby discovering a stunning molecular choreography that has never been seen before.

By breaking the choreography continuum into steps, the thiazolium ring of ThDP exhibits two major states planar and non-planar on the basis of bond angles, bond lengths and electronic configurations. The planar forms are correlated with carbanion/carbene in-termediates, while the bent (non-planar) are correlated with several types of diradicals. In contrast to the planar thiazolium that was the sole one reported in almost all ThDP-containing enzymes, the indentification of the non-planar thiazoliums is virtually unexpected, thus motivating Professor Li to mull over that are the non-planar thiazolums authentic intermediates essential to the ThDP-assisted reactions?

These findings and thinking backed them to put forward a novel diradical mechanism for TK-catalyzed keto-transferring reactions, which perfectly accounts for the thiazolium ring bending effect and the facile C-C bond breakage/formation of sugars.

To validate the propsoed working model, they performed deuterium-exchanging ex-periments alongside delicate analysis of Mass Spectrometry, NMR, EPR and quantum computation. Together concludes that the thiazolium ring in ThDP is an ensemble of carbanion, singlet carbene, and diradicals (π-radicals) in a dynamic manner.

It has been well noted that vitamin B1 is the precursor of ThDP involved in an assortment of biochemical reactions in addition to maintaining the homeostasis of the blood sugar level in our body. Despite that vitamin B1 is highly water-soluble and unretainable, it is still unclear how vitamin B1 is metabolized. Given the new chemical properties revealed in their study, the team further pointed out that the half-life of ThDP is subject to the substrate-level regulation, thus shaping a brand-new concept to the field.

Summing up the above, the multiple complexes and the mechanisms disclosed by the team can serve as a working model for future quantitative kinetics and computational validation by using a quantum mechanical/molecular mechanical method. The new concept may also be applicable to some other ThDP-dependent enzymes for attractive prospects in biocat-alytic applications and/or drug design.

There are two related publications to be read online at:



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