Almaaqal University Biochemistry PDF

Almaaqal University Metabolism of Protein and Amino Acids Dr/ Wael Sobhy Darwish Biochemistry PhD Lec-12  Conversion Of Amino Acids To Specialized Products Amino acid are precusors...

Almaaqal University Metabolism of Protein and Amino Acids Dr/ Wael Sobhy Darwish Biochemistry PhD Lec-12  Conversion Of Amino Acids To Specialized Products Amino acid are precusors of many nitrogen containing compounds that have physiological functions which incluide: Glycine is non-essential - glucogenic amino acid. Functions Glycine is the precursor for: - Haeme - Hippuric acid - Glutathione - Glyoxylic acid - Purine bases - Bile salts - Collagen -Creatine - Serine – Neurotransmitter. 1. Haeme: is the pigment, which combines with globin protein to form hemoglobin. - Glycine reacts with Succinyl CoA to form a substance called amino levulonic acid (ALA) which finally converted to heme.  Degradation of haem In adults 250–400 mg of bilirubin is produced daily. 70-80% 70–80% is derived from degradation of the haem moiety of haemoglobin 20-25% 20–25% is derived from the hepatic turnover of haem proteins, such as myoglobin, cytochromes and catalase. The life span of red blood cells, about 120 days Normally, senescent red blood cells are phagocytosed by cells of the reticuloendothelial system; particularly (spleen and liver) 1-globin is converted into amino acids, which in turn are recycled or catabolised as required, 2- haem is oxidised by the haem oxygenase system. Oxidation splits the porphyrin ring to give biliverdin, releasing ferric iron (Fe3+) and (CO). Released iron is recycled.  Biliverdin reductase converts biliverdin to bilirubin using a reduction reaction. Bilirubin is unconjugated and must be transported to the liver by bounding to albumin. At the sinusoidal surface of the liver, unconjugated bilirubin detaches from albumin and is transported through the hepatocyte membrane by facilitated diffusion. Within the hepatocyte, bilirubin is bound to, cytosolic Y protein (ligandin) and cytosolic Z protein. These binding decreases the efflux of bilirubin back into the plasma, and therefore increases net bilirubin uptake. Inside hepatocyte, two molecules of glucuronic acid attached covalently to bilirubin by glucuronyl transferase enzyme (UGT-1), generating (bilirubin di-glucuronide).  These glucuronic acid-attached to bilirubin are termed "Conjugated Bilirubin" and are now water soluble. Conjugated Bilirubin travels down the GI tract The normal GI bacterial flora convert the majority of conjugated bilirubin to colorless "Urobilinogen" and a small amount to yellow-colored "Urobilin". About 90% of urobilinogen is excreted with the feces; about 10% is resorbed and enters the blood stream where it is once again recaptured by hepatocytes and re-excreted in the bile. The majority of urobilin is also excreted in the feces, giving it the characteristic brown color after converted to stercobilin; a small minority is resorbed by the GI mucosa and excreted by the kidneys, giving urine its yellowish color.  Glutathione Structure: Glutathione is a Tripeptide formed of three amino acids: glutamate, cysteine and glycine. Forms of glutathione: - Two Forms are present: reduced (G-SH) and oxidized (G-SS-G). SH group indicates the sulfhydryl group of the cysteine and it is the most active part of the molecule. Functions of glutathione: 1- Defense mechanism against certain toxic compounds (Detoxification). 2- Absorption of amino acid 3- Protect against cell damage and hemolysis of RBCs: Glutathione breakdown the hydrogen peroxide (H2O2) which causes cell damage and hemolysis. 4- Activation of some enzymes. 5- Inactivation of insulin hormone  Creatine (N-methyl-guanidoacetate): - Synthesis of Creatine: It is synthesized from three amino acids: glycine, arginine, and methionine. This occurs by two reactions in kidney, liver and pancreas. - Functions of Creatine: - Creatine is phosphorylated to Creatine phosphate this occurs in muscles. - Creatine phosphate acts as a store of high energy phosphate in muscles and used during muscle exercise (as it can give phosphate to ADP to form ATP).  Creatine kinase enzyme (CK): Also called Creatine phospho kinase (CPK): - This enzyme catalyses the formation of creatine phosphate. Present in 3 isoenzymes 1) CK-MM: from skeletal muscles and its serum level is elevated in muscle disease 2) CK-MB: mainly from heart muscle and its serum level is elevated in myocardial infarction. 3) CK-BB: derived from brain and its serum level is elevated in damage of brain cells. - Degradation of Creatine phosphate → (gives creatinine): a) Creatine phosphate loses water and phosphate molecules to form creatinine. b) Creatinine is the end product of creatine metabolism and is normally rapidly removed from the blood and excreted by the kidney in urine. - Diagnostic importance of determination of plasma creatinine: a) Estimation of plasma creatinine (0.6 - 1.4 mg/dl) is used as kidney function test. b) High blood creatinine and urea levels are sensitive indicators of renal failure.   PHENYLALANINE Phenylalanine is a Ketogenic and glucogenic essential amino acid. Functions: phenylalanine is the precursor for Tyrosine In liver This reaction needs phenylalanine hydroxylase enzyme and tetrahydrobiopterin as coenzyme. Deficiency of either phenylalanine hydroxylase or dihydrobiopterin reductase results in a disease called Phenylketonuria. Definition: It is inherited deficiency of phenylalanine hydroxylase enzyme. Atypical phenylketonuria: deficiency of dihydrobiopterin reductase enzyme. Effects (signs and symptoms): 1) Mental retardation. 2) Increased blood phenylalanine 3) Failure to walk and talk. 4) Hyperactivity and tremors. 5) Failure to grow. 6) Skin lesion e.g. eczema. Frequency of phenylketonuria: is 1 in 10,000 live births Diagnosis of phenylketonuria By measuring blood phenylalanine by a test called Guthrie test to the infants at 4th day Prevention of phenylketonuria: a) Any infant proved to have abnormal high level of blood phenylalanine, should feed milk containing very low amount of phenylalanine. b) This regimen of diet is maintained up to 6 years of age when a high concentration of phenylalanine has no longer effect on brain cells.  Hereditary Tyrosinemia (tyrosinosis): Definition: It is inability to metabolise tyrosine and p-hydroxy phenylpyruvate. Cause: deficiency of tyrosine α-Ketoglutarate transaminase and p-hydroxy- phenylpyruvate oxidase enzymes Forms of tyrosinemia: a) Acute: where there is diarrhea, vomiting and failure to grow. Death from liver failure occurs within 7 months. b) Chronic: occurs later in life. Liver cirrhosis and hepatic carcinoma are common. There is also a mild mental retardation. Prevention and treatment: Feeding the affected infant and children a diet containing very low levels of tyrosine and phenylalanine (precursor of tyrosine). Alkaptonuria: Definition: benign disease resulting from deficiency of homogentisate oxidase enzyme. Effects: Homogentisate increases and causes: a) Deposition in joints causing arthritis b) Deposition in connective tissue causing generalized pigmentation. c) Excreted in large amounts in urine, that is oxidized in the air giving the dark urine Albinism: Definition : hereditary deficiency of tyrosine hydroxylase enzyme in melanocytes. Effects: defective synthesis of melanin pigments. Eye, skin and hair are affected. - Types of albinism: according to the site affected: a) Eye: ocular albinism. b) Skin: cutaneous albinism. c) Eye and skin: oculo-cutaneous albinism  Cystinuria (cystine - lysinuria): Definition : hereditary disease characterized by amino aciduria (excessive excretion of cystine together with basic amino acids; lysine, Arginine, and ornithine. Cause: defective renal tubular reabsorption of these 4 amino acids. Cystine may precipitated in renal tubules forming renal stones.