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NitrogenMetabolism Dr.KevinAhern Nitrogen Metabolism Nitrogen Forms in the Body Nitrogen Balance Critical Body Must Make and Break Down Amino Acids Nitrogen Also Needed for Synthesis of Nucleotides (ATP, GTP, CTP, UTP, dATP, dCTP, dGTP, dTTP) Non-Protein Amino Acids Ornithine Citrulline Sarcosine Other Nitrogen-Containing Compounds Choline Vitamins Carnitine Ornithine Citrulline Sarcosine Excretion of Nitrogen Amino Acids Through Transamination Make Nitrogen Mobile Toxicity of Ammonia means Nitrogen Balance is Critical in the Body Excretion Ammonotelic - Excrete Ammonia - Fish Uricotelic - Excrete Uric Acid - Birds Ureotelic - Excrete Urea - Most Vertebrates, Some Invertebrates Produced by Amino Acid Catabolism Used in Urea Cycle Produced by Purine Catabolism Produced by Urea Cycle Ammonia Uric Acid Urea α-ketoglutarate Family Transamination to Make Glutamate Amino Acid X α-ketoacid #1 α-keto Acid #1 + Amino Acid X Amino Acid #1 + α-keto Acid X Amino Acid #2 α-ketoacid X Glucose-Alanine Cycle Alanine Metabolism High Ammonia Glucose-Alanine Cycle Important for Removing Ammonia Transamination in Liver Creates Glutamate Breakdown of Glutamate Yields Amine for Urea Production Alanine Carries Amine to Liver Low Ammonia Urea Cycle Primarily Occurs in Liver. Also in Kidney Consists of 4 Cycle Reactions and 1 Feeder Reaction Feeder Reaction Incorporates 1 Molecule of Ammonia and 1 CO2 Per Turn Cycle Reaction Provides 1 Amine from an Amino Acid Output of Cycle is 1 Molecule of Urea Per Turn The Net Reaction Per Turn of the Cycle is 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMP Urea Cycle Carbamoyl Phosphate Synthetase Reaction The Source of Ammonium Ion is Glutamine or Glutamate Requires Action of Glutaminase (Glutamine) or Glutamate Dehydrogenase (Glutamate) Glutamine + H2O Glutamate + H2O + NADP+ Glutamate + NH3 α-ketoglutarate + NH3 + NADH + H+ H2O + CO2 HCO3- + NH4+ H2O + CO2 HCO3- + NH4+ 2 ATP + HCO3− + NH4+ <=> 2 ADP + Carbamoyl phosphate + P Ornithine Transcarbamoylase Reaction Carbamoyl Phosphate Enzyme Expressed Only in Liver Most Commonly Deficient Enzyme in Urea Cycle X-linked Inheritance In Severe Deficiency, Ammonia Levels Rise to Lethal Levels if Untreated Liver Transplant and Low Protein Diet Most Common Treatments + Ornithine Ornithine Transcarbamoylase Citrulline + Pi Phosphate Citrulline Transport to Cytoplasm Citrulline Movement to Cytoplasm Requires Ornithine-Citrulline Translocase Antiport - Moves Citrulline Out, Ornithine In Needed for Both Parts of Urea Cycle Deficiency of Translocase Mimics Defective Ornithine Transcarbamoylase Condition at Birth More Serious Than Adult Onset Argininosuccinate Synthetase Two Step Reaction First, AMP Attaches to Amine-rich End of Citrulline Next, Aspartate Displaces the AMP The Product is L-argininosuccinate Reaction is Rate Limiting Step of Cycle Gene Expression of Enzyme Reduced by Arginine, Increased by Citrulline Enzyme Defects Lead to Citrullinemia - Accumulation of Ammonia Treated with Low Protein Diet, Arginine Supplementation 1 2 Argininosuccinate Lyase Important for Production of Arginine Argininosuccinate Lyase Source of Fumarate Deficiency Like That of Other Urea Cycle Enzymes - Ammonia Excess Bond Cleaved To Proteins or Remainder of Urea Cycle + Argininosuccinate Lyase Argininosuccinic Acid To Citric Acid Cycle Arginine Fumaric Acid Arginase Co-expressed with Nitric Oxide Synthase in Smooth Muscle Increased Arginase Activity Reduces Nitric Oxide Production Nitric Oxide Relaxes Smooth Muscle and Facilitates Erection of Penis Deficiency of Arginase Rarest of Urea Cycle Enzymes Two Forms of Arginase Provide Some Backup When One Deficient To Mitochondria Excreted To Complete Cycle Through Ornithine Citrulline Translocase Cut + + H2O Arginase Arginine Urea Ornithine Urea Cycle Citrulline Alternate Means of Producing Citrulline - Nitric Oxide Synthase Bypasses Mitochondrial Part of Urea Cycle & Produces Nitric Oxide Arginine is Substrate for Reaction 2 L-arginine + 3 NADPH + 1 H+ + 4 O2 Nitric Oxide Synthase 2 Citrulline +2 Nitric Oxide + 4 H2O + 3 NADP+ Nitric Oxide Important Signaling Molecule in Humans - Vasodilation Viagra works by enhancing signaling through the nitric oxide pathway in the penis Nitrites Nitrite formed by Ionization of Nitrous Acid (HNO2) or Reduction of Nitrates Nitrite Used to Cure Meats and Prevent Botulism Can Be Reduced to Nitric Oxide in Hypoxic Conditions In Human Diet 80-90% from Reduction of Nitrates in Vegetables Nitrates in Vegetables From Fertilizers or Plant Stresses Nitrite Readily Forms Cancer-Causing Nitrosamines in Stomach Acid Nitrites Oxidize Hemoglobin’s Iron From Ferrous (II) to Ferric(III) State - Unable to Carry Oxygen - Can be Serious Nitrosamines Nitrosamines Produced by Reaction of Nitrites and Secondary Amines, Such as Proline Strong Acids (Stomach) or High Temperatures of Frying Favor Production Found in Processed Meats, Beer, Cigarette Smoke, Chewing Tobacco Formation Inhibited by Vitamin C 2H+ H2NO2+ → H2O + NO+ Nitrous Acid Ion Nitrosonium Ion Nitrite → NO+ + H Secondary Amine Nitrosamine Nitrosamines Nitrosamines Form DNA Adducts and Cause Cancer in Many Animal Species Likely Carcinogens In Humans Evidence for Gastric and Esophageal Cancer Risk Nitrosamines in Tobacco Form From Nicotine NNK is Nicotine Derived and Important in Carcinogenesis NNK in Tobacco and E-cigarettes NNK Activation by P-450 Activated Signaling Cascades & Uncontrolled Growth Nicotine-derived nitrosamine ketone (NNK) (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) Reactive Nitrogen Species Reactive Nitrogen Species Can Arise from any of the Molecules Described Here The Most Potent Reactive Nitrogen Species is Peroxynitrite Reactive Nitrogen Species Peroxynitrite is Formed from Nitric Oxide and Superoxide Peroxynitrite Can Readily React with DNA and Protein, Causing Damage Cysteine Side Chains are Most Easily Oxidized Tyrosine Side Chains of Proteins Can Be Nitrosylated Transition Metals, Such as in Hemoglobin, Myoglobin, and Cytochromes Can Be Oxidized ·NO + O2·− Nitric Oxide Superoxide ONOO− Peroxynitrite Amino Acid Metabolism Introduction There are 20 Common Amino Acids in Proteins Plus One Rare One No One Single Pathway for Amino Acid Metabolism Synthesis Pathways are Grouped According to Common Anabolic Precursors α-ketoglutarate Serine Aspartate Aromatic Pyruvate Histidine Essential Amino Acids Must Be in Diet Non-Essential Ones Can be Made by Organism Essential vs Non-Essential Varies in Humans α-ketoglutarate Family Transamination Plays an Important Role α-keto Acid #1 + Amino Acid X Amino Acid #1 + α-keto Acid X α-ketoglutarate Family Transamination to Make Glutamate Amino Acid X α-ketoacid #1 α-keto Acid #1 + Amino Acid X Amino Acid #1 + α-keto Acid X Amino Acid #2 α-ketoacid X α-ketoglutarate Family Glutamine Synthesis Uses Glutamine Synthetase α-ketoglutarate Family - Arginine Synthesis Citrulline + Aspartate Four Pathways to Make it ATP AMP + 2 Pi Argininosuccinate NADP+ NADPH + O2 Arginine Citrulline + Nitric Oxide + H2O H2O ADMA Demythlation Ornithine + Urea Deficiency of the Enzyme Arginase Leads to the Genetic Disease of Argininemia Accumulation of Arginine and NH4+ in the Blood Arginine ADMA Serine Family Two Main Paths Lead to Serine 1. From 3-phosphoglycerate (Connection to Glycolysis) 3-PG + NAD+ 3-phosphohydroxypyruvate Glutamate α-ketoglutarate O-phosphoserine H 2O Serine + Pi Serine Family 2. Exchanging Carbon with Glycine and Folates (Important for Folate Recycling) Serine + Tetrahydrofolate Glycine + N5,N10-Methylene Tetrahydrofolate + H2O Serine Family Methionine Cysteine Metabolism Multiple Ways of Making Cysteine Primary Means Tied to Methionine Catabolism Methionine Adenosyltransferase. ATP Pi + PPi SAM Transmethylase Acceptor CH3-Acceptor SAH S-adenosylhomocysteine Hydrolase High Blood Levels - Cardiovascular Disease, Stroke Risk Deficiency Leads to Homocystinuria H2O Adenosine Homocysteine Serine Cystathionine β-synthase Cystathionine Cystathionase H2O NH4+ β-ketobutyrate Cysteine Serine Family Other Cysteine Metabolism Serine L-cystine L-cysteic Acid Acetyl-CoA 2 NADH + 2H+ H2S CoA-SH 2 NAD+ Sulfite O-acetyl-L-serine H2S L-cysteine + Acetate 2 Cysteine L-cysteine Serine Family Selenocysteine Metabolism Sometimes Called 21st Amino Acid Not Specified Directly in Genetic Code Uses Stop Codon with Unusual Structure Synthesized from Serine on tRNA Serine + tRNA Non-SER tRNA SERtRNA SEL-A Incorporation Into Proteins SEL-D SELtRNA AspartateFamily All Family Members Arise from Aspartate Aspartate Can be Made from One of Them - Asparagine Numerous Paths Lead to Aspartate Transamination Hydrolysis Urea Cycle Glutamate + Oxaloacetate Asparagine + H2O Argininosuccinate + AMP Reversal of Reaction α-ketoglutarate + Aspartate Aspartate + NH4+ Toxic Aspartate + Citrullyl-AMP Aspartate Family Asparagine Metabolism Synthesis Breakdown Aspartate + Glutamate + ATP Asparagine + H2O Asparagine Synthetase Asparagine + α-ketoglutarate + AMP + PPi Energetically Costly Essentially Not Reversible Asparaginase Aspartate + NH4+ Toxic Aromatic Family Outline Tryptophan Melatonin Serotonin Niacin Auxins Phenylalanine Phenylketonuria Tyrosine Catecholamines Thyroid Hormones Melanin Aromatic Family Tryptophan, Phenylalanine, and Tyrosine Each Derived from Phosphoenolpyruvate and Erythrose-4-phosphate Synthesis Pathways Complex Each Involves Shikimic Acid and Chorismic Acid Phenylalanine and Tyrosine Pathways Overlap Hormones and Neurotransmitters Made from Each Aromatic Family Tryptophan Interesting Regulation of Synthesis in Bacteria Attenuation - All 5 Genes on One Operon When Tryptophan High, Transcription of Operon Aborts Early When Tryptophan Low, Transcription of Operon Continues Through All Genes Molecules Made from Tryptophan Melatonin Circadian Rhythm Sensing Affects Mood, Sleep, Blood Pressure Production Affected by Blue Light Melatonin Serotonin Serotonin Neurotransmitter Causes Vasoconstriction Enhances Memory/Learning, Contributor to Happy Feelings Niacin Niacin Vitamin B3 Nicotinamide Derived From it - Part of NAD+/NADH & NADP+/NADPH Deficiency Leads to Pellagra Auxins Indole-3-Acetic Acid Most Important Indole-3-Acetic Acid Stimulate Cell Division and Rooting in Plants Aromatic Family Phenylalanine (PHE) An Essential Amino Acid and Precursor of Tyrosine PHE Hydroxylase Catalyzes Formation of Tyrosine from PHE Deficiency of the Enzyme PHE Hydroxylase Causes Phenylketonuria High PHE Levels Cause Damage to Brain Treatable by Reducing PHE Levels Nutrasweet Contains PHE Aromatic Family Tyrosine (TYR) Not Essential if PHE Present Precursor of Catecholamines - L-Dopa, L-Dopamine, Norepinephrine, and Epinephrine Donates Electrons to Reduce Chlorophyll in Photosystem II Forms Radical in Ribonucleotide Reductase L-Norepinephrine CO2 L-Norepinephrine L-Ephinephrine Aromatic Family Tyrosine Metabolism L-Dopa Precursor to Dopamine Crosses Blood-Brain Barrier Used to Treat Parkinson’s Disease Dopamine Neurotransmitter Inhibits Norepinephrine Release in Blood Vessels - Acts as Vasodilator Reduces Insulin Production in Pancreas Deficiency Causes Parkinson’s Disease Links to Schizophrenia and ADHD Norepinephrine Hormone and Neurotransmitter Works Through Noradrenergic Receptors Fight or Flight Response Increases Heart Rate and Blood Pressure Epinephrine (Adrenalin) Hormone Actions Similar to Norepinephrine Fight or Flight Response Increases Heart Rate and Blood Pressure Aromatic Family Secretion of Thyroglobulin Tyrosine is a Precursor of Thyroid Hormones Export from Cell Iodide Export & Oxidation Iodination Thyroglobulin Breakdown Transport Into Cell Transport Into Blood Aromatic Family Tyrosine Metabolism Thyroid Hormones All are Se-Containing Enzymes Deiodinases T3 (Triiodothyronine) More Active Form T4 (Thyroxine) More Abundant Form Aromatic Family Tyrosine Metabolism Melanin - Oxidized and Polymerized Tyrosine Benzoquinone Portion of Coenzyme Q Tyrosine Unit From Tyrosine Further Polymerization Aromatic Family Tyrosine Metabolism & Disease Tyrosinemia - Problems with Tyrosine Catabolism Type I Type II Type III Alcaptonuria - Black Urine Disease Treatments Restricted TYR/PHE Diet Liver Transplant Tyrosine Tyrosine Transaminase Type II p-hydroxyphenylpyruvate p-hydroxyphenylpyruvate Dioxygenase Type III Homogentisate Alcaptonuria Alcaptonuria 4-Maleylacetoacetate 4-Fumarylacetoacetate Type I 4-fumarylacetoacetase Fumarate + Acetoacetate Pyruvate Family Alanine Metabolism Most Easily Produced from Pyruvate - Transamination Byproduct of Catabolism of Valine, Leucine, and Isoleucine Glucose-Alanine Cycle Glutamate + Pyruvate Alanine Transaminase α-ketoglutarate + Alanine Pyruvate Family Leucine (LEU) /Valine (VAL) /Isoleucine (ILE) Metabolism Branched Chain Amino Acids (BCAAs) Several Common Steps Start with Decarboxylation and Attachment of Two Carbon Piece to TPP Valine and Leucine Pathways Involve Attachment of Two Carbon Piece to Pyruvate Isoleucine Pathway Involves Attaching Two Carbon Piece to α-ketobutyrate Penultimate Products - α-ketoisocaproate (LEU), α-ketoisovalerate (VAL), and α-keto-βmethylvalerate (ILE) Each is Transaminated to Make Final Amino Acid Isoleucine Leucine Valine Pyruvate Family Leucine (LEU) /Valine (VAL) /Isoleucine (ILE) Metabolism Synthesis Feedback Regulated Through Threonine Deaminase Starting Material for ILE Makes Starting Material for ILE Starting Material for VAL & LEU Used by All Three High VAL Favors ILE High ILE Favors VAL & LEU Pyruvate Family Histidine (HIS) Metabolism Most Complex of All the Amino Acids Overlaps Nucleotide Metabolism with Ribose-5-Phosphate & PRPP 10 Steps in Pathway Second Enzyme of Pathway (ATP-phosphoribosyltransferase) Feedback Inhibited by Histidine Histidine Amino Acid Catabolism Three Categories 1. Glycogenic - Broken Down to Glycolysis/ Gluconeogenesis Intermediates 2. Ketogenic - Broken Down to Acetyl-CoA 3. Both - Makes Intermediates in Both Pathways Glycogenic Alanine, Cysteine, Glycine, Serine Asparagine, Aspartate, Arginine Histidine, Proline, Glutamine Glutamate, Methionine, Valine Ketogenic Lysine, Leucine Both Threonine,Tryptophan, Tyrosine, Phenylalanine, Isoleucine AminoAcidCatabolism Most Diseases of Amino Acid Metabolism Arise from Problems with Catabolism Alcaptonuria - Phenylalanine and Tyrosine Methylmalonic Acidemia - Methionine, Threonine, Isoleucine and Valine Maple Syrup Urine Disease - Valine, Leucine, Isoleucine Homocystinuria - Methionine Tyrosinemia - Tyrosine Argininemia - Arginine Hypermethioninemia - Methionine Hyperlysinemia - Lysine Glycine Encephalopathy - Glycine Propionic Acidemia - Methionine, Threonine, Isoleucine and Valine Hyperprolinemia - Proline