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Theoretical studies on models of lysine-arginine cross-links derived from α-oxoaldehydes: a new mechanism for glucosepane formation

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Abstract

Availability and high reactivity of α-oxoaldehydes have been approved by experimental techniques not only in vivo systems but also in foodstuffs. In this article we re-examine the mechanism of glucosepane formation by using computational model chemistry. Density functional theory has been applied to propose a new mechanism for glucosepane formation through reaction of α-oxoaldehydes with methyl amine (MA) and methyl guanidine (MGU) models of lysine and arginine residues respectively. This non enzymatic process can be described in three main steps: (1) Schiff base formation from methyl amine, methyl glyoxal (MGO) (2) addition of methyl guanidine and (3) addition of glyceraldehyde. We show that this process is thermodynamically possible and presents a rate-determining step with a reasonable free energy barrier equal to 37.8 kcal mol-1 in water solvent. Comparisons were done with the mechanism formation of GODIC (glyoxal-derived imidazolium cross-link) and MODIC (methyl glyoxal-derived imidazolium cross-link), two other important cross-links in vivo.

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Notes

  1. In this stage of the reaction, there will be a competition between glucose and α-oxoaldehydes in the nucleophilic attack on amino groups in the proteins. Glucose, because of high stability in its cyclic form, will be less subject to the nucleophilic attacks compared to the α-oxoaldehydes and since α-oxoaldehydes are up to 20,000-fold more reactive than glucose [50]. Therefore, glucosepane can likely be derived through reaction of the α-oxoaldehydes with lysine and arginine amino acids

  2. Following the comment of a reviewer, we tested the influence of two different isomers of MGU (see tautomers C and E in Scheme 4) on the reaction profile in second step of cross-linking process. We found that activation barriers are to be in different values when tautomers are involved in the process (see Figure S1). It is worth noting that isomer F cannot be involved in the process actively since Lederer and Klaiber definitely excluded formation of MODIC or GODIC via endocyclic nitrogens of arginine residues (see 34 for more detail)

  3. Following the comment of a reviewer, we computed entropic contributions on free energy profile in the gas phase and solvent for glucosepan. Our calculations revealed that this contribution has maximum values at the beginning of any step; (i.e, in addition of MA, MGU and GLA on GO/MGO, Int4 and Int8, respectively) whereas in any other steps enthalpic contributions overcome on entropy penalty (see Table S1). Therefore, it can be concluded that entropic contribution in most cases can not affect the reaction profile (exception in beginning of each steps) while that enthalpic terms are more effective and determining on the proceeding of reaction

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Acknowledgments

The financial support of Research Council of Shahid Beheshti University is gratefully acknowledged. Rasoul Nasiri would like to thank the Ministry of Science, Research, and Technology of Iran for financial support. Many thanks also go to Martin Field and Andrew Greene for their helpful discussions.

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Correspondence to Mansour Zahedi.

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Nasiri, R., Zahedi, M., Jamet, H. et al. Theoretical studies on models of lysine-arginine cross-links derived from α-oxoaldehydes: a new mechanism for glucosepane formation. J Mol Model 18, 1645–1659 (2012). https://doi.org/10.1007/s00894-011-1161-x

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