Biochemistry: Amino Acid Conversion to Specialized Products PDF

BIOCHEMISTRY AMINO ACID CONVERSION to SPECIALIZED PRODUCTS BRENDO V. JANDOC, M.D. 1A...

BIOCHEMISTRY AMINO ACID CONVERSION to SPECIALIZED PRODUCTS BRENDO V. JANDOC, M.D. 1A CATECHOLAMINES OVERVIEW Biologically Active Amines - dopamine neurotransmitters in - norepinephrine (noradrenalin) brain & ANS & Functions: - epinephrine (adrenalin) synthesized in the adrenal medulla 1. Building Blocks for proteins - methylated derivative of FUNCTIONS: 2. Precursors of many nitrogen- norepinephrine  regulators of carbohydrate containing compounds of and lipid metabolism important physiologic functions  response to fright, exercise,  porphyrins cold, low blood glucose levels  neurotransmitters  increased degradation of  hormones glycogen & TAG  purines  increases cardiac output &  pyrimidines blood pressure SYNTHESIS STEP 1: rate-limiting step, mixed-function oxidase TYROSINE HYDROXYLASE  Abundant in: central nervous system, sympathetic ganglia, adrenal medulla  Allosteric  Negative Effectors: dopamine, norepinephrine, epinephrine  Cofactor: Tetrahydrobiopterin NADPH: reductant in the regeneration of tetrahydrobiopterin from dihydrobiopterin STEP 2 DOPA DECARBOXYLASE (Aromatic Amino Acid Decarboxylase)  pyridoxal phosphate-dependent  forms 3,4-dihydroxyphenylethylamine (dopamine) from dopa STEP 3 DOPAMINE Βeta-HYDROXYLASE  contains copper  forms norepinephrine  Requirements: Ascorbate & Molecular Oxygen TYROSINE STEP 4 precursor of several biologically important compounds PHENYLETHANOLAMINE N-METHYLTRANSFERASE  in the adrenal medulla  forms epinephrine  Synthesis: induced by glucocorticoids from the surrounding adrenal cortex hormone  inhibited by epinephrine Neurotransmitter; basal gangila Neurotransmitter; Sympathetic NS pigment hormone Trans |ABACCO, ASSISTIN, ALDERITE, BALANZA, BAYAS, BIANG 1 of 4  BIOCHEMISTRY AMINO ACID CONVERSION to SPECIALIZED PRODUCTS DEGRADATION f. Degenerative Process Inactivated by: decreased dopamine synthesis (acetylcholine not affected) > acetylcholine : Monoamine Oxidase (MAO) dopamine imbalance > movement disorder - oxidative deamination g. Genetics: mutation in gene encoding α-syneclein (presynaptic protein -found in neural tissues, gut, liver involved in neuronal plasticity) -functions as “safety valve” in neural h. Signs of Parkinson’s Disease: appear when dopamine level decreases tissues, inactivate excess by 80% in the nigrostriatal system neurotransmitter molecules i. Causes of Parkinsonism Catechol-O-Methyltransferase ia. Viral Infection - O-methylation: S-adenosylmethionine ib. High Level of Mn++ in Miners ic. Drugs Metabolic Products:  reserpine - excreted as conjugates with sulfate or  neuroleptics, antipsychotics glucuronic acid  β-N-methyl-amino-L-alanine (toxin) Vanillylmandelic acid (VMA)  1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine - excretion levels, aid in the diagnosis  in intravenous drug users of adrenal pheochromocytomas  byproduct in the synthesis of synthetic heroine derivative (tumors that produce large amounts of j. Treatment catecholamines)  Dopamine: does not cross blood-brain barrier Metanephrine  Levodopa (L-Dopa): can cross blood-brain barrier, converted to Normetanephrine dopamine by dopa decarboxylase, mostly decarboxylated in the periphery (1% to brain)  Carbidopa: inhibits peripheral dopa decarboxylase, does not cross blood-brain barrier  Bromocriptine: dopamine receptor agonist, simulate effects of dopamine irreversibly or reversibly inactivate the enzyme > neurotransmitters escape degradation > accumulate within the presynaptic neuron > leak into the synaptic space > norepinephrine and serotonin receptor activation > antidepressant action of the drugs PARKINSON’S DISEASE rarely occurs before age 40 a. Characteristics: tremor, bradykinesia b. Key Pathologic Characteristic: degeneration of substancia nigra supposed to produce and use dopamine c. Dopaminergic Neurons: nigrostriatal, mesolimbic, mesocortical, tuberohypophyseal system d. Lewy Bodies - characteristic neuropathologic finding in affected areas of the brain - eosinophilic intraneuronal cytoplasmic inclusion bodies - consists of neurofilaments and other amorphous materials e. Overall Process When Dopamine Act as Neurotransmitter i. Synthesis ii. Storage in synaptic vesicles MELANINS - entry of dopamine driven by pH gradient established by a protein  Melanins: biologic pigment occurring in the eye, hair, skin in the vesicular membrane pumping protons into the vesicle at the  Melanocytes: synthesize melanin to protect underlying cells from harmful expense of ATP sunlight effects iii. Release by exocytosis  Tyrosine Hydroxylase (Tyrosinase): uses copper as cofactor iv. Binding to its postsynaptic receptors  Albinism: defect in tyrosinase v. Reuptake by a high-affinity transporter, uses ATP > dopamine recycled vi. Degradation - within the synaptic cleft and presynaptic terminal - MAO- degrade dopamine Type A Enzyme inhibited by clorgyline Type B Enzyme inhibited by selegiline Trans |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 2 of 4  BIOCHEMISTRY AMINO ACID CONVERSION to SPECIALIZED PRODUCTS THYROXINE AND TRIIODOTHYRONINE some reduced by aldehyde reductase (alcohol dehydrogenase) > 5-hydroxytryptophol (5-HTOL)  Alcohol Ingestion > increased NADH level > favored reduction pathway > changes urine (5-HIAA : 5-HTOL ratio) b. Biosynthesis of Melatonin  hormone produced by the pineal gland  effect on the hypothalamic-pituitary system  methylation of N-acetylserotonin by O-methyl transferase using S- adenosylmethionine c. Nicotinamide Ring of NAD+ synthesized from tryptophan a. Formed in the thyroid follicular cells b. Iodination of tyrosine residues (which are in peptide linkage in chains of the GLUTAMATE protein thyroglobulin) precursor of ϒ-aminobutyrate (GABA) c. Formation of monoiodo- and diiodotyrosine residues > react forming T3 and GABA T4 - inhibitory transmitter in the brain and spinal cord d. Iodinated thyroglobulin stored in the lumen of thyroid follicles > hydrolysis - metabolized within neurons to succinate bypassing the α-ketoglutarate of T3 and T4 > secreted into the circulation dehydrogenase step of the TCA cycle e. T3 - more active form - may be the only form to bind to receptors in cell nuclei - 2/3 of plasma T3 arises from T4 deiodination in the liver TRYPTOPHAN Precursor of serotonin, melatonin, oxidized nicotinamide-adenine dinucleotide (NAD+) A. Metabolism of Serotonin (5-Hydroxytryptamine) - largest amount found in intestinal mucosal cells - small amount in platelets & central nervous system Multiple Physiologic Roles pain perception; normal and abnormal behaviors including affective disorders; regulation of sleep, temperature, blood pressure; potent vasoconstrictor, smooth muscle contraction stimulator Synthesis  by neurons whose cell bodies are chiefly located in the hypothalamus, brain stem, pineal HISTIDINE gland, chromaffin cells of the GIT precursor of histamine  Tryptophan Hydroxylase A. Functions catalyzes the rate-limiting step 1. Potent vasodilator requires tetrahydrobiopterin as the 2. Neural transmitter reductant and which forms 5- 3. Allergic reactions, trauma > mast hydroxytryptophan (5-HTP) cells > histamine  Decarboxylase: decarboxylation 4. Chemical messenger mediating wide > serotonin range of cellular responses a. Allergic responses b. Inflammatory responses c. Gastric acid secretion d. Neurotransmission in parts of the brain 5. No clinical applications - agents that interfere with histamine action have important therapeutic applications Storage in granules in association with ATP 6. Secreted by mast cells as a result of Degradation a. Allergic reactions  MAO - oxidative deamination of 5-HT > 5-hydroxyindoleacetaldehyde b. Trauma bulk of 5-hydroxyindoleacetaldehyde is oxidized by Antihistamine Drugs aldehyde dehydrogenase > 5-hydroxyindoleacetic acid (5-HIAA) - structural similarity to histamine - prevent the physiologic changes caused by histamine Trans |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 3 of 4  BIOCHEMISTRY AMINO ACID CONVERSION to SPECIALIZED PRODUCTS B. Biosynthesis 2. Excreted Creatinine - reaction requires pyridoxal phosphate - proportional to creatine phosphate content of the body > estimate muscle C. Histamine degradation mass 1. S-adenosylmethionine methylation of 1 of the imidazole nitrogens and - muscle mass (paralysis, dystrophy) > urinary creatinine content subsequent oxidation by MAO - efficiently cleared from the plasma by the kidneys 2. Direct oxidation by MAO - renal malfunction > increased blood creatinine - adult male excretes about 15 mmol creatinine/day GLUTATHIONE - constancy of excretion > test reliability of collected 24 hour urine sample (if  tripeptide, redox-active complete)  formed rom glutamate, cysteine, glycine - no diurnal variation > basis for calculating urinary output of other  exists as monomeric reduced form or dimeric oxidized form (held substances together by a disulfide bone between cysteine sulfhydryls) A. Structure POLYAMINES - peptide bond to glutamate is formed with the ϒ-carboxyl group (rather the - formed from ornithine carboxyl on the α-carbon) - polycations at physiologic pH B. Functions - associated with negatively charged cell components (ex: membranes, nucleic 1. Sulfhydryl Buffer acids) - regulate the redox state of the cell by maintaining the equilibrium between A. Putrescine the oxidized and reduced forms 1. Ornithine Decarboxylase 2. Amino Acid Transport - inducible, extremely short half-life - across the plasma membrane in certain cells - decarboxylate ornithine > putrescine 3. Cofactor for Certain Enzymes B. Spermidine - ex: glutathione peroxidase - aminopropyl residue of decarboxylated S-adenosylmethionine condenses - uses reduced glutathione to detoxify peroxides with putrescine > spermidine C. Spermine CREATINE PHOSPHATE - condensation of spermidine and aminopropyl residue > spermine  phosphorylated derivative of creatine  found in muscle (amount is proportional to muscle mass)  high-energy phosphate-storage compound  reversibly donate phosphate group to ADP > ATP 1. Enzyme: Creatine Kinase provides a rapidly mobilized high-energy phosphate reserve > maintain intracellular ATP level during the first few minutes of intense muscular contraction 2. Creatine Kinase in the Plasma Arginine, Ornithine, and Proline Metabolism - indicative of tissue damage, used in - putrescine and spermine synthesis occurs in both mammals and bacteria diagnosis of myocardial infarction - arginine phosphate of invertebrate muscle functions as a phosphagen A. Synthesis analogous to creatine phosphate of mammalian muscle formed from Glycine, Arginine, S- adenosylmethionine (methyl group donor) CARNOSINE and ANSERINE B. Degradation  dipeptides 1. Creatine and Phosphocreatine  found in muscles in some species - spontaneously cyclize > creatinine > urine  functions are not clear - slow rate  formed from histidine and β-alanine - constant A. Carnosine - present olfactory pathway in the brain - none in cardiac muscles - condensation of histidine with β-alanine > carnosine B. Anserine - not found in human skeletal muscles - carnosine methylation by S-adenosylmethionine > anserine Trans |ABACCO, ALDERITE, ASSISTIN, BALANZA, BAYAS, BIANG 4 of 4