Structural and biochemical basis of methylmalonate semialdehyde dehydrogenase ALDH6A1

Background:ALDH6A1,a member of the ALDH family,plays a crucial role in the catabolic pathways of valine and thymine.Dysregulation of ALDH6A1 expression has been linked to a variety of diseases.Methylmalonate semialdehyde dehydrogenase deficiency(MMSDH deficiency),an autosomal recessive disorder,arises from muta-tions in the ALDH6A1 gene.Additionally,ALDH6A1 has emerged as a biomarker for several types of severe cancer.Despite its significance,the structural and biochemical mechanisms of ALDH6A1 remain poorly explored.Methods:The apo form of ALDH6A1 was solved by cryo-electron microscopy.Enzyme activity assay and thermal stability assays were conducted to elucidate the bio-chemical properties of ALDH6A1 and to find an agonist of ALDH6A1,Alda-1.The binding pattern of ALDH6A1 and nicotinamide adenine dinucleotide(NAD^(+))was explored by molecular docking.Results:This study presents,for the first time,a structural analysis of ALDH6A1 in its apo form at a resolution of 2.75Å,uncovering a tetrameric architecture with tightly interacting monomers.Our findings indicate that Alda-1,an agonist of ALDH2,enhances ALDH6A1 activity as well.Moreover,ALDH6A1,compared with ALDH2,exhibits a unique binding model with NAD^(+).Conclusion:Our results shed light on the structural aspects of ALDH6A1 and provide valuable insights into its catalytic mechanism.The precise determination of the ALDH6A1 structure holds promise for the development of targeted therapies aimed at restoring ALDH6A1 activity,thus providing potential value for individuals affected by related diseases.

HLA-G and single nucleotide polymorphism(SNP)associations with cancer in African populations:Implications in personal medicine

The immune system plays an important role in protecting the body against malignancy.During cancer immunoediting,the immune system can recognize and keep checking the tumor cells by down-expression of some self-molecules or by increasing expression of some novel molecules.However,the microenvironment created in the course of cancer development hampers the immune ability to recognize and destroy the transforming cells.Human Leukocyte Antigen G(HLA-G)is emerging as immune checkpoint molecule produced more by cancer cells to weaken the immune response against them.HLA-G is a non-classical HLA class I molecule which is normally expressed in immune privileged tissues as a soluble or membrane-bound protein.HLA-G locus is highly polymorphic in the non-coding 3′untranslated region(UTR)and in the 5′upstream regulatory region(5′URR).HLA-G expression is controlled by polymorphisms located in these regions,and several association studies between these polymorphic sites and disease predisposition,response to therapy,and/or HLA-G protein expression have been reported.Various polymorphisms are demonstrated to modulate its expression and this is increasingly finding more significance in cancer biology.This review focuses on the relevance of the HLA-G gene and its polymorphisms in cancer development.We highlight population genetics of HLA-G as evidence to espouse the need and importance of exploring potential utility of HLA-G in cancer diagnosis,prognosis and immunotherapy in the currently understudied African population.