Investigation on a MMACHC mutant from cblC disease: The c.394C&gt;T variant

Passantino, Rosa; Mangione, Maria Rosalia; Ortore, María Grazia; Costa, Maria Assunta; Provenzano, Alessia; Amenitsch, Heinz; Sabbatella, Raffaele; Alfano, Caterina; Martorana, Vincenzo; Vilasi, Silvia

doi:10.1016/j.bbapap.2022.140793

Cited by 1 publication

(1 citation statement)

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“…The most commonly identified mutations include c.271dupA, c.394C > T, and c.331C > T. The mutations c.271dupA and c.331C > T have been associated with EO disease, and c.394C > T is primarily associated with LO disease [6,18,19]. Apart from this, a wide range of missense mutations in the MMACHC gene have been identified that have an impact on protein stability as well as Cbl and GSH binding [20]. The vast majority of reported missense mutations are concentrated in the Cbl binding region and are likely to interfere with Cbl binding.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Glutathione with MMACHC Arginine-Rich Pocket Variants Associated with Cobalamin C Disease: Insights from Molecular Modeling

Antony,

Baby,

Ali

et al. 2023

Biomedicines

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Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is required by the body to metabolize cobalamin (Cbl). Due to its complex structure and cofactor forms, Cbl passes through an extensive series of absorptive and processing steps before being delivered to mitochondrial methyl malonyl-CoA mutase and cytosolic methionine synthase. Depending on the cofactor attached, MMACHC performs either flavin-dependent reductive decyanation or glutathione (GSH)-dependent dealkylation. The alkyl groups of Cbl have to be removed in the presence of GSH to produce intermediates that can later be converted into active cofactor forms. Pathogenic mutations in the GSH binding site, such as R161Q, R161G, R206P, R206W, and R206Q, have been reported to cause Cbl diseases. The impact of these variations on MMACHC’s structure and how it affects GSH and Cbl binding at the molecular level is poorly understood. To better understand the molecular basis of this interaction, mutant structures involving the MMACHC-MeCbl-GSH complex were generated using in silico site-directed point mutations and explored using molecular dynamics (MD) simulations. The results revealed that mutations in the key arginine residues disrupt GSH binding by breaking the interactions and reducing the free energy of binding of GSH. Specifically, variations at position 206 appeared to produce weaker GSH binding. The lowered binding affinity for GSH in the variant structures could impact metabolic pathways involving Cbl and its trafficking.

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