PreprintArticleVersion 1This version is not peer-reviewed
Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants
Version 1
: Received: 29 June 2024 / Approved: 1 July 2024 / Online: 2 July 2024 (02:28:47 CEST)
How to cite:
de la Mora-de la Mora, I.; García-Torres, I.; Flores-López, L. A.; López-Velázquez, G.; Hernández-Alcántara, G.; Gómez-Manzo, S.; Enríquez-Flores, S. Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants. Preprints2024, 2024070097. https://doi.org/10.20944/preprints202407.0097.v1
de la Mora-de la Mora, I.; García-Torres, I.; Flores-López, L. A.; López-Velázquez, G.; Hernández-Alcántara, G.; Gómez-Manzo, S.; Enríquez-Flores, S. Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants. Preprints 2024, 2024070097. https://doi.org/10.20944/preprints202407.0097.v1
de la Mora-de la Mora, I.; García-Torres, I.; Flores-López, L. A.; López-Velázquez, G.; Hernández-Alcántara, G.; Gómez-Manzo, S.; Enríquez-Flores, S. Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants. Preprints2024, 2024070097. https://doi.org/10.20944/preprints202407.0097.v1
APA Style
de la Mora-de la Mora, I., García-Torres, I., Flores-López, L. A., López-Velázquez, G., Hernández-Alcántara, G., Gómez-Manzo, S., & Enríquez-Flores, S. (2024). Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants. Preprints. https://doi.org/10.20944/preprints202407.0097.v1
Chicago/Turabian Style
de la Mora-de la Mora, I., Saúl Gómez-Manzo and Sergio Enríquez-Flores. 2024 "Functional and Structural Implications of Methylglyoxal-Induced Non-Enzymatic Post-Translational Modifications in Human Triosephosphate Isomerase Variants" Preprints. https://doi.org/10.20944/preprints202407.0097.v1
Abstract
Protein glycation impacts enzymatic activity, disrupts metabolic processes, and is associated with chronic degenerative diseases. The human glycolytic enzyme triosephosphate isomerase (HsTIM, TPI1, or HsTPI) is associated with various disorders, such as enzymopathies originating from mutations. It also possesses moonlighting functions and is now recognized as a cancer marker. Previous reports of HsTPI mutants have demonstrated a significant increase of methyl-glyoxal (MGO) due to trioses accumulation. We compared how catalytic activity exerts differen-tial kinetic and structural stability effects due to mutations by tracking fluorescent argpyrimi-dine adduct (ARGp) through interaction with Arginine-MGO. Circular dichroism and fluores-cence spectroscopy were explored in HsTPI-WT and mutants HsTPI-C217K “Like-WT”, HsTPI-N16D accumulated in cancer, and HsTPI-E104D human deficiency mutant, by cysteines accessibility and time loss of activity and unfolding propensity in mutant enzymes with aggre-gates refractory to proteolysis in the C217K. Our study sheds new light on the increased suscep-tibility of mutants to generate MGO adducts due to TPI isomerization of MGO precursor sub-strates. Nevertheless, mutations enhance a negative feedback cycle, in which accumulated MGO access promotes accelerated loss of activity that leads to unfolding and aggregation. The cumu-lative and accelerated increase in MGO adducts, which probably are responsible for the patho-logical state in this TPI variant, are partially reversed by adding MGO-scavenger molecules.
Keywords
advanced glycation end products (AGEs); metabolic dysfunction; protein relation structure-function; spectroscopic analysis; conformational changes; catalytic aging; molecular wear; enzymatic rescue
Subject
Medicine and Pharmacology, Pathology and Pathobiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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