ET eT ounY Metabolism of Branched chain amino acids Fo coo coo coo i | 1 1 2 UN-C— MN —C—H “HN-C—H | cu cu H-C—CH, “\ I mc Cn, cu mc Cn, Valine Leucine il aiTE RSC Tea) + Allthe three are essential amino acids. coo | * Valine is glucogenic. WN-C- * Leucine is purely ketogenic. is + while Isoleucine is both /\ ketogenic and glucogenic. ne (, * They are alternate source of fuel to the brain.Ee oe Branched chain amino acids initially Baye undergo a common pathway and then cekologtae acd 2 diverge to result in different end products. mee: outamie aca The first three reactions are common to all = branched chain amino acids BCKAS LTransamination Tec] NAO onsapach ; 2. Oxidative decarboxylation by a- keto z acid dehydrogenase This is the regulatory enzyme. It is multi enzyme complex. Co Sane ‘ enzymes are TPP, Lipoamide, FAD,NAD, and 2Motrybutyy-CoA a, Coenzyme A .Keto acids are converted to corresponding Acyl CoA thioesters. ‘Suecinyl-CoA, ‘ ‘caty-CoA, Propiony-Con alaeBCAAs 2 3. Dehydrogenation o-Kotogutaric ald BCA, Ina series of reactions that follow Gieninecdl wore Be 258 Valine is converted to Propiony! CoA, > i Leucine produces Acetyl CoA and BCKAS acetoacetate , Isoleucine is degraded to Propionyl CoA and Acetyl CoA aot Coonzyme & ADH. cor Isobutyry-coA, 5 Isovalery-Con, 2-Methyoutynyh CoA Succinyl-CoA, ——— ‘Acoty.con, Propiony-Con, aMetabolism of branched chain a.acid, histidine and Polyamines.mp4 3. Dehydrogenation . Acyl Con Dehydrogenare PEE ceriviccinnicsk Tayi Gun of ae PER atvylactroncetyi CoA yf Pracontcon sea eR aiaMetabolism of branched chain a.acid, histidine and Polyamines.mp4 Maple syrup urine disease ( MSUD ) < Also called Branched chain ketonuria, Urine of affected individuals smells like ‘maple syrup or burnt sugar-hence the name. Defect: Defect is in enzyme branched chain a- keto acid dehydrogenase . This causes ‘ blockade in conversion of a- keto acid to respective acyl coA thioesters. Plasma and urine levels of branched chain amino acids and their keto acids are highly elevated, Accumulation of this causes impairment in transport and function of other amino acidsa-Ketoglutaric acid Glutamic acid : BCKAs ‘ Branched-chain] NAD+ Coenzyme A foto ach * dehydrogenase | NADH co: He Isobutyryl-Coa, Isovaleryl-Con, 2-Methylbutyryl-GoA, | ® Succinyl-CoA, ‘Acetyl-CoA,, Propionyl-CoA ;Te om Clinical features: 4 Disease starts in the first week of life. Characterised by convulsions, Severe mental retardation, vomiting , acidosis, coma and death within Iweek after birth. Diagnosis. Urine : contains branched chain keto acids ° Rothera’s test will be positive. Enzyme analysis in cells: Preferably within the 1* week of life. Treatment: Give diet low in branched chain amino acids. High doses of Thiamine.( Mild variant of MSUD shows response to this )Metabolism of branched chain a.acid, histidine and Polyamines.mp4 Symptoms of Maple Syrup Urine + Vomiting Disorder: + lack of energy (leghargy) iba ormenis delay, + Avoiding food + Urine that smells like maple syrup + Ifuntreated, Maple Syrup Urine Disease can lead to seizures, coma, and death.Isovaleric Aciduria Here Leucine metabolism is affected. 7 5 Defect : Isovaleryl CoA dehydrogenase. Clinical features: 1 Affected individuals show offensive odor of urine . Mild mental retardation and acidosis seen. Diagnosis: Urine shows high levels of abnormal metabolites.PUY Metabolism of HistidineMetabolism of Histidine Histidine is semi- essential basic amino acid. It is Glucogenic NH, © - -_ 1 : Contains imidazole ring. Dp CH;—C— COOH R HN. I H Responsible for maximum buffering action. FT icaMetabolism of Histidine 1. Non oxidative deamination Ht by Histidase to form Urocanic acid. 2 2. Urocanate is then hydrated to form imidazole propionate 3. Which is then hydrolyzed to form Formimino Glutamic acid (FIGLU). FT Bae) ene Ligne (sas) rocoto 07] (Grosanase] ‘amidanlone 5 propionate Ls row) certs +t (Gamat form: Niro ee© _ Metabolism of Histidine 4, FIGLU transfers its formimino osc] Cae ” group to Tetra hydro folic acid to form rcedote Glutamic acid nom Gieanaa ” Folic acid deficiency blocks this step of histidine metabolism. As a result, FIGLU levels are elevated in patients 1 Senin game.) with Folic acid deficiency. werent Df Pin erie] Histidine load test is done to identify raf folate deficiency. ‘Glucogen patwayMetabolism of branched chain a.acid, histidine and Polyamines.mp4 Histamine : Histidine on decarboxylation form Histamine. > Effects of histamine are smooth muscle contraction, increase vascular permeability. increase secretion of gastric juice. > Histamine causes fall in BP. > Excessive production of histamine causes asthma and allergic reactions. Dae a)Tee) Disorders of Histidine metabolism of Histidine Histidinaemia + erro refute [Urocanie aeiduria Characterized by 1 Tmidazolor¥ propionate Skeretion of urocanate. Saas Formincfoglutamate = = > Characterized by t o Sreretion of FEELU. . THE Folic ocid deficiencyDisorders of Histidine metabolism Histidinemia : Inheritance ; Autosomal recessive Defect: Deficiency of enzyme Histidase. Clinical features. Defective speech development and mental retardation. Diagnosis ~ Histidine levels are elevated in blood. Management: Low histidine diet is advised. Urocanic aciduria: Defect: Deficiecy of enzyme urocanase Urocanic acid and histidine are elevated in urine. Clinical manifestations are minimal. uleen rr Polyamines Biological amines made Up of multiple amino acids called polyamines They are Putrescine, Spermine and spermidine. = polyamines are positively charged at physiological pH since they have 4 multiple amino groups. Spermine and spermidine were first discovered from human semen and hence the name,Metabolism of branched chain a.acid, his oun 6 Functions of polyamines + Polyamines are involved in regulation of transcription and translation. + They act as growth factor and function in cell proliferation and * growth. + Polyamines are involved in stabilization of intact cells , subcellular organelle and membranes.a Biosynthesis of polyamines. = Ornithine and S- adenosyl methionine serve as = precursor molecules for synthesis of polyamines. ail Ornithine is first decarboxylated by Ornithine decarboxylase to putrescine 1 wry Putrescine condenses with decarboxylated SAM to generate spermidine and spermine. soerir,2 DEM) ( Difluromethyl ornithine) is a powerful wy hibitor of polyamine synthesis. Eg, Of suicide inhibition, eal Ser eon20 Degradation of polyamines Polyamines are degraded in liver cells by polyamine aan oxidase. It converts spermine to spermidine and then to putrescine. Putrescine is then oxidized to Lendl CO, and ammonia. way Clinical significance of polyamines seeming 2 Polyamines and their derivatives have application in diagnosis and treatment of cancer. 3 Their levels are increased in body fluids of cancer patients. wry seme, 3