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Mutation in coenzyme binding sites and diseases Mutation in coenzyme binding sites and diseases

Mutation in coenzyme binding sites and diseases - PowerPoint Presentation

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Mutation in coenzyme binding sites and diseases - PPT Presentation

VBC607 Unit2 PG 27112020 onethird of the mutations in a gene is an increased Michaelis constant or Km decreased binding affinity of an enzyme for the coenzyme or substrate which in turn lowers the rate of the reaction ID: 911176

enzyme acid plp binding acid enzyme binding plp mental retardation mutations catalyzes gene homocysteine cystathionine mitochondria pyruvate protein glyoxylate

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Slide1

Mutation in coenzyme binding sites and diseases

VBC-607

Unit-2

P.G.

27.11.2020

Slide2

one-third of the mutations in a gene is an increased Michaelis constant, or Km, (decreased binding affinity) of an enzyme for the coenzyme or substrate, which in turn lowers the rate of the reactionin addition to direct changes in the amino acids at the coenzyme binding site, some mutations affect the conformation of the protein, thus causing an indirect change in the binding sitegenetic disease or polymorphism involving derangement of metabolism, multiple forms of the disease exist that reflect slight increases in the enzyme KmOf the 3870 enzymes catalogued in the ENZYME database 860 (22%) use a cofactorduring aging, oxidation deforms many proteins, thereby decreasing their affinity for their substrates or coenzymesThe deformation include direct protein oxidation, adduction of aldehydes from lipid peroxidation, and, in the case of membrane proteins, decreases in fluidity of oxidized membranes

Am J Clin Nutr 2002;75:616

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gyrate atrophy of the choroid and retinaDefect in Ornithine aminotransferase which is a PLP-dependent mitochondrial matrix protein that catalyzes the breakdown of ornithine to δ-pyrroline-5-carboxylic acid, which is then converted into prolinean autosomal recessive diseaseOrnithine accumulates 10- to 15-fold when the enzyme is defectivethe defective enzyme has a Km defect for PLPalanine-to-valine substitution at codon 222 (Ala226→Val)

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homocystinuriaDefect in Cystathionine β-synthase (CBS) of the transsulfuration pathway catalyzes the PLP-dependent condensation of homocysteine and serine to form cystathionineaccumulate homocysteine in the blood and urine and display a wide range of symptoms that appear to be due to homocysteine toxicity, including mental retardation, vascular and skeletal problems, and optic lens dislocation>100 pathogenic mutations (including >70 missense mutations) that span all 7 exons of the CBS gene affects the enzyme activity

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X-linked sideroblastic anemiaDefects in Erythroid specific δ-aminolevulinic acid synthase, which is present in the mitochondria and catalyzes the condensation of glycine and succinyl-CoA to form δ-aminolevulinic acid, the first reaction in the series of reactions that makes heme for incorporation into hemoglobinThe mutation is responsible for inherited form of sideroblastic anemia, which is X-linkedAs Fe is transported to the mitochondria whether or not it is combined with heme, deficiencies in heme lead to iron deposits in erythroblast mitochondria and increased ringed

sideroblasts in the marrowExon 9 contain the PLP binding site and point mutations Gly291→Ser, Ile471→Asn, (663G→A) in the ALAS2 gene lead to altered co enzyme binding

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xanthurenic aciduria and mental retardationDefect in Kynureninase, which is a PLP-requiring enzyme involved in tryptophan degradationCatalyzes the conversion of kynurenine and 3-hydroxykynurenine to anthranilic acid and 3-hydroxyanthranilic acid, respectivelyMutations cause an excessive urinary output of 3-hydroxykynurenine and kynurenine

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seizures in newborns and intelligence quotient deficitsDefects in Glutamic acid decarboxylase, a PLP enzyme, converts glutamic acid to γ-aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the central nervous system Defects in GAD result in seizures in newbornsA treatment of asthma, theophylline, depresses PLP concentrations, and may cause seizures by decreasing γ-aminobutyric acid production

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cystathioninuria, mental retardation, and diabetesDefects in γ-cystathionase (cystathionine γ-lyase) which converts cystathionine into cysteine and α-ketobutyrate, completing the transfer of sulfur from homocysteine to cysteineresult in cystathionine accumulation in the urine and tissuesClinically cause of mental retardation, convulsions, thrombocytopenia, nephrogenic diabetes insipidus, and diabetes mellitus

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hyperoxaluria and renal failureDefects in Alanine–glyoxylate aminotransferase which is a liver-specific enzyme that uses a PLP cofactor to transfer the amino group from alanine to glyoxylate, forming serine and pyruvateresults in an accumulation of glyoxylate that is converted to oxalate, resulting in renal deposits of calcium oxalate and renal failure

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Cohen syndromeDefects in β-Alanine α-ketoglutarate transaminase which is involved in the formation of malonic semialdehyde from β-alanineCharacterized by hypotonia, midchildhood obesity, mental deficiency, and facial, oral, ocular, and limb anomalies

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Leigh diseaseDefects in Pyruvate decarboxylase that catalyze the conversion of pyruvate to acetyl-CoA Results into lethal lactic acidosis, psychomotor retardation, central nervous system damage, ataxia, muscle fiber atrophy, and developmental delayThe gene encoding the E1α peptide of the E1 subunit (pyruvate decarboxylase), which binds TPP, is located on the X chromosomemutation was shown to increase the Km of the E1 subunit for TPP and reduce the Vmaxmutation Gly89→Ser in exon 3 resulting in a decreased affinity for TPP

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variegate porphyria and motor neuropathyDefects in Protoporphyrinogen oxidase, a mitochondrial flavoprotein, catalyzes the oxygen-dependent oxidation of protoporphyrinogen IX to protoporphyrin IXresults in variegate porphyria which involves various neuropsychiatric symptoms, including bulbar paralysis, quadriplegia, and motor neuropathyThe Arg59→Trp mutation affects the FAD binding motif

Slide13

hemophiliaDefects in γ-Glutamyl carboxylaseWith bound vitamin K in the presence of oxygen and carbon dioxide it converts glutamic acid residues to γ-carboxyglutamic acid residuesMutation Leu394→Arg raises Km by 5 times for vitamin K hydroquinone

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phenylketonuria IIDefects in Phenylalanine hydroxylase utilizes tetrahydrobiopterin to convert phenylalanine into tyrosinelead to mental retardation as a result of the accumulation of phenylalanine and its neurotoxic metabolitesMutation Val388→Met, has a reduced enzymatic activity and a 3.7-fold increased Km for tetrahydrobiopterin