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Hemoglobin
international journal for hemoglobin research
Volume 43, 2019 - Issue 1
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Original Article

Insights into the Progression of Labile Hb A1c to Stable Hb A1cvia a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process

, , , , &
Pages 42-49 | Received 24 Oct 2018, Accepted 23 Feb 2019, Published online: 07 May 2019
 

Abstract

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A1c (the conjugate acid of the Schiff base). Labile Hb A1c can then undergo slow, largely irreversible, formation of stable Hb A1c (the Amadori product). Stable Hb A1c is measured to assess diabetic progression after labile Hb A1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A1c and the slow rate of NEG.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This study was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences [grant number P20GM103408]. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health, Bethesda, MD, USA. Further support was provided by the Departments of Biological Sciences and Chemistry and the College of Science and Engineering at Idaho State University, Pocatello, ID, USA.

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