Amino Acid Metabolism Disorders PDF

AMINO ACID METABOLISM DISORDERS Dr.Ula Abbas Zeki 1  1 Objectives of this lecture: Explain the biochemical basis of inborn errors of amino acid metabolism Reviewing clinical sign...

AMINO ACID METABOLISM DISORDERS Dr.Ula Abbas Zeki 1  1 Objectives of this lecture: Explain the biochemical basis of inborn errors of amino acid metabolism Reviewing clinical sign and symptoms related to the disease. The following diseases were discussed Phenylketonuria Maple syrup urine disease Albinism Homocystinuria Alkaptouria 2  2 They are inborn errors of metabolism caused by mutations that generally result in abnormal proteins, most often enzymes. inherited defects may be expressed as a total or partial loss of enzyme activity. Loading… Without treatment, amino acid disorders almost invariably result in intellectual disability or other developmental abnormalities as a consequence of harmful accumulation of metabolites 3  3 C A B CX A X BX D (harmful product to the body)  body) A. Phenylketonuria PKU is the most common clinically encountered inborn error of amino acid metabolism caused by a deficiency of phenylalanine hydroxylase PAH enzyme. Loading… 5 5 6 6 7  7 Biochemically, PKU is characterized by 1. hyperphenylalaninemia. 2. Deficiency of tyrosine 8  8 Characteristics of classic PKU: Elevated phenylalanine: present in elevated concentrations in tissues, plasma, and urine. CNS symptoms: MR, failure to walk or talk, seizures, hyperactivity, tremor, microcephaly, and failure to grow are characteristic findings in PKU. Hypopigmentation: Patients with PKU often show a deficiency of pigmentation (fair hair, light skin color, and blue eyes). 9  9 10  10 Loading… 11 11 12  12 B. Maple syrup urine disease (MSUD) rare disorder in which there is a partial or complete deficiency in branched-chain α-keto acid dehydrogenase enzyme BCKD that oxidatively decarboxylate leucine, isoleucine, and valine. These BCAA and their corresponding α-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. 13  13 The disease characterized by feeding problems, vomiting, ketoacidosis, changes in muscle tone, neurologic problems that can result in coma (primarily because of the rise in leucine) a characteristic maple syrup–like odor of the urine because of the rise in isoleucine. 14  14 C. Albinism Albinism refers to a group of conditions in which a defect in tyrosine metabolism results from an absent or defective copper-requiring tyrosinase enzyme, which cause deficiency in the production of melanin. These defects result in the partial or full absence of pigment from the skin, hair, and eyes. In addition to hypopigmentation, affected individuals have vision defects and photophobia (sunlight hurts their eyes). They are at increased risk for skin cancer. 15 15 16 16 17  17 D. Homocystinuria group of disorders involving defects in the metabolism of homocysteine Hcy. The most common cause of homocystinuria is a defect in the enzyme cystathionine β-synthase, which converts Hcy to cystathionine 18 18 19  19 Biochemically characterized by : High urinary levels of Hcy. High plasma levels of Hcy and methionine. Low plasma levels of cysteine. 20  20 Patients exhibit dislocation of the lens ,skeletal anomalies (long limbs and fingers), intellectual disability, and an increased risk for developing thrombi (blood clots). Thrombosis is the major cause of early death in these individuals 21  21 E. Alkaptonuria Alkaptonuria is a rare organic aciduria involving a deficiency in homogentisic acid oxidase enzyme, resulting in the accumulation of homogentisic acid (HA), an intermediate in the degradative pathway of tyrosine 22 22 23  23 The condition has three characteristic symptoms ) homogentisic aciduria (the urine contains elevated levels of HA, which is oxidized to a dark pigment (alkapton) on standing, ) early onset of arthritis in the large joints, ) Deposition of black pigment in cartilage and collagenous tissue. The patients usually asymptomatic until about age 40 years. 24 24 25 25 26  26 Thank you Any question? 27 Conversion of amino acids to specialized products Lec 4 Dr Ula Abbas Objectives of this lecture : Describe porphyrin and heme synthesis Definition of porphyria and its types. ILO: K2, S12, A0 2  In addition to serving as building blocks for proteins, amino acids are precursors of many nitrogen-containing compounds that have important physiologic functions. These molecules include porphyrins, neurotransmitters, hormones, purines, and pyrimidines. 3 PORPHYRIN METABOLISM 4  Porphyrins are cyclic compounds that readily bind metal ions, usually ferrous (Fe2+) or ferric (Fe3+) iron. The most prevalent metalloporphyrin in humans is heme, consists of one Fe2+ coordinated in the center of tetrapyrrole ring of protoporphyrin IX. 5  Heme is the prosthetic group for hemoglobin (Hb), myoglobin, the cytochromes, the cytochrome P450 (CYP) monooxygenase system, catalase, nitric oxide synthase, and peroxidase (hemeproteins ) 6  Structure of Porphyrin Porphyrins are cyclic planar molecules formed by the linkage of four pyrrole rings through methenyl bridges 7 Heme biosynthesis 8  The major sites of heme biosynthesis are the liver, which synthesizes a number of heme proteins (particularly the cytochrome P450 proteins), and the erythrocyte-producing cells of the bone marrow, which are active in Hb synthesis. In the liver, the rate of heme synthesis is highly variable, while heme synthesis in erythroid cells is relatively constant and is matched to the rate of globin synthesis. Over 85% of all heme synthesis occurs in erythroid tissue, and it is controlled by erythropoietin and the availability of intracellular iron 9 The initial reaction and the last three steps in the formation of porphyrins occur in mitochondria, whereas the intermediate steps of the biosynthetic pathway occur in the cytosol. Mature red blood cells (RBC) lack mitochondria and are unable to synthesize heme. 10  Heme (hemin) effects When porphyrin production exceeds the availability of the apoproteins that require it, heme accumulates and is converted to hemin by the oxidation of Fe²⁺ to Feᵌ⁺ Hemin decreases the amount (and, thus, the activity) of ALA synthase by repressing transcription of its gene, increasing degradation of its mRNA, and decreasing import of the enzyme into mitochondria. 12 Porphyrias  Porphyrias are a rare group of inherited (or sometimes acquired) defects of haem synthesis Caused by deficiency of one of the enzymes of the haem synthetic pathway resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors 14  Clinical manifestations The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can be further classified as acute or chronic. 15 a.Chronic porphyria: Porphyria cutanea tarda the most common porphyria, is a chronic disease of the liver and erythroid tissues. The disease is associated with a deficiency in uroporphyrinogen decarboxylase. 16  b.Acute hepatic porphyrias: This type lead to accumulation of ALA and porphobilinogen. 17 c. Erythropoietic porphyrias: characterized by skin rashes and blisters that appear in early childhood. 18 Any questions? OTHER NITROGEN- CONTAINING COMPOUNDS ‐ “ ‐ Objectives : Describe types of catecholamine, its biological role ,its synthesis and catabolism ‐ Definition of histamine and its synthesis ‐ Definition of serotonin ,its synthesis and biological function ‐ Definition of creatine. Its synthesis and degradation ‐ Definition of melanin ,its synthesis and biological function ‐ ILO: K2, S12, A0 21 A. Catecholamines 22 © Dopamine, norepinephrine (NE), and epinephrine (or, adrenaline) are biologically active amines that are collectively termed catecholamines. © Dopamine and NE are synthesized in the brain and function as neurotransmitters. © Epinephrine is synthesized from NE in the adrenal medulla. © All catecholamines are synthesized from tyrosine 23  Function: Outside the CNS, NE and its methylated derivative, epinephrine, are hormone regulators of carbohydrate and lipid metabolism. NE and epinephrine are released from storage vesicles in the adrenal medulla in response to fright, exercise, cold, and low levels of blood glucose to prepare the individual for stress and are often called the “fight-or-flight” reactions Catecholamines are inactivated by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 24 b. Serotonin 25 ‐ also called 5-hydroxytryptamine (5-HT) ‐ Serotonin is synthesized from tryptophan. ‐ synthesized and/or stored at several sites in the body, and the largest amount is found in the intestinal mucosa. ‐ Smaller amounts occur in the CNS, where it functions as a neurotransmitter, and in platelets. ‐ Has multiple physiologic roles including pain perception and regulation of sleep, appetite, temperature, blood pressure, cognitive functions, and mood (causes a feeling of well-being). 26 c. Histamine 27 ▪ is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions and gastric acid secretion. ▪ formed by decarboxylation of histidine in a reaction requiring PLP. ▪ It is secreted by mast cells as a result of allergic reactions or trauma. 28 D. Creatine 29 ‐ Creatine phosphate (also called phosphocreatine), the phosphorylated derivative of creatine that found in muscle >>> the amount of creatine phosphate in the body is proportional to the muscle mass. ‐ It is a high-energy compound that provides a small reserve of high- energy phosphates that can be reversibly transferred to ADP to maintain the intracellular level of ATP during the first few minutes of intense muscular contraction. 30 31  Synthesis ‐ Creatine is synthesized in the liver and kidneys. ‐ Animal products are dietary sources. ‐ Creatine is reversibly phosphorylated to creatine phosphate by creatine kinase, using ATP as the phosphate donor. 32  Degradation Creatine and creatine phosphate spontaneously cyclize at a slow but constant rate to form creatinine, which is excreted in the urine. The amount of creatinine excreted is proportional to the total creatine phosphate content of the body and can be used to estimate muscle mass. Rise in blood creatinine is a sensitive indicator of kidney dysfunction, because creatinine normally is rapidly cleared by the kidney from the blood and excreted. adult male excretes ~1–2 g of creatinine/day. 33 34  “ E. Melanin 35 ‐ Melanin is a pigment that occurs in several tissues, particularly the eye, hair, and skin. ‐ It’s synthesized from tyrosine in melanocytes (pigment forming cells) of the epidermis. ‐ It functions to protect underlying cells from the harmful effects of sunlight. ‐ A defect in melanin production results in albinism. 36 Thank you! 37