of advanced glycation end products; ROS -reactive oxygen species; SNCA -synuclein alpha; sRAGE -soluble receptor of advanced glycation end products; TTR -transthyretin; TKtransketolase; TNF -tumor necrosis factor-α; TPP -thiamine pyrophosphate Review THE ROLE OF ADVANCED GLYCATION END PRODUCTS IN VARIOUS TYPES OF NEURODEGENERATIVE DISEASE:A THERAPEUTIC APPROACH Abstract: Protein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies Unauthenticated Download Date | 5/11/18 1:17 PM

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Alpha1-antitrypsin (alpha1-AT) is a 52 kDa sialoglycoprotein. The function of alpha1-antitrypsin is to protect the lower respiratory tract of lungs from proteolytic degradation by neutrophil elastase. Severe genetic deficiency of alpha1-AT is associated with early onset emphysema and liver diseases. alpha1-AT also exhibits anti-inflammatory activities independent of its protease inhibitor function. There are over 90 genetic variants of human alpha1-antitrypsin. These variants occur due to amino acid substitution / deletion which results in charge differences. Based on charge differences these variants have been identified by isoelectric focusing. The two most common deficiency variants are S and Z. The S variant migrates anodal to Z variant. The Z variant migrates most cathodal in isoelectric focusing, hence named Z. In Z variant, the beta-sheet A undergoes expansion, therefore it can easily accept the reactive site loop of a second alpha1-AT molecule and consequently form polymers of alpha1-AT. These polymers of alpha1-AT aggregate in the hepatocytes and show liver and lungs diseases. Contrary to this, the S variant of alpha1-AT is not associated with any significant clinical disease because the conformation of the inhibitor is not altered significantly. The Z related pathologies could be treated by liver transplantation, augmentation therapy, gene therapy, peptide therapy and chemical chaperone therapy. In addition to common deficiency variants, there are several rare deficiency variants of alpha1-AT like Siiyama, Mmalton, Mprocida, Mheerlen, Mmineral springs, Mnichinan, Pduarte, Wbethesda Zaugsberg, and Zbristol. In Siiyama, Mmalton, Mnichinan and Zaugsberg, the beta-sheet A is present in an open state therefore these variants readily undergo polymerization and consequently show aggregation in the hepatocytes. In Mprocida, Mheerlen, Mmineral springs, Pduarte and Wbethesda the conformation is altered significantly therefore these variants become conformationally less stable and thereby undergo intracellular proteolysis. These rare genetic variants show lungs and / or liver disease. There are several null variants of alpha1-AT that are not detected either at the stage of transcription or translation. The examples of some of the null variants are QOcardiff, QOhong kong, QOgranite falls, QObellingham, QOmattawa, QObolton, and QOludwigshafen. The molecular basis of deficiency of these variants also forms the theme of this review.

Antibiotic resistance in gram-negative bacteria has emerged as a major health threat that occurs because these bacteria actively produce β-lactamases responsible for the inactivation of β-lactam antibiotics. The first β lactamase was reported in E. coli back in 1940, before the release of the first antibiotic penicillin in clinical settings. Later on, large numbers of β-lactamases have been discovered in Gram-positive, Gram-negative bacteria as well as mycobacteria. Currently, numerous three-dimensional structures of serine and metallo-β-lactamases have been solved. The serine β-lactamases essentially consist of two structural domains (an all α and an α/β domain) and the active site is located at the groove between the two domains. The catalysis of serine β-lactamase proceeds via acylation and deacylation reactions. The three dimensional structure of metallo-β-lactamases displayed a common four layer "αβ/βα" motif, with a central "ββ"- sandwich by Zn2+ ion(s), and two α-helices are located on the either side. The active site of metallo-β-lactamases contain either 1 or 2 Zn2+ ions, which is coordinated to metal ligating amino acids and polarized water molecule(s) necessary for the hydrolysis of β-lactam antibiotics. Keeping the above views in mind, in this review we have shed light on the current knowledge of the structures and mechanisms of catalysis of serine and metallo-β-lactamases. Moreover, mutational studies on β-lactamases highlight the importance of the active site residues and residues in the vicinity to the active site pocket in the catalysis. To combat bacterial infections more effeciently novel inhibitors of β-lactamase in combination with antibiotics have been used which also form the theme of the review.

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Influenza A virus (H1N1), a genetic reassortment of endemic strains of human, avian and swine flu, has crossed species barrier to human and apparently acquired the capability of human to human transmission. Some strains of H5N1 subtype are highly virulent because NS1 protein inhibits antiviral interferon α/β production. Another protein NS2 mediates export of viral ribonucleoprotein from nucleus to the cytoplasm through export signal. In this paper, we have studied structure-function relationships of these proteins of H1N1 subtype and have determined the cause of their pathogenicity. Our results showed that non-conservative mutations slightly stabilized or destabilized structural domains of NS1 or NS1-dsRNA complex, hence slightly increased or decreased the function of NS1 protein and consequently enhanced or reduced the pathogenicity of the H1N1 virus. NS2 protein of different strains carried non-conservative mutations in different domains, resulting in slight loss of function. These mutations slightly decreased the pathogenicity of the virus. Thus, the results confirm the structure-function relationships of these viral proteins.