nitrogen metabolism - oregon state...
TRANSCRIPT
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NitrogenMetabolism
Dr.KevinAhern
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Nitrogen Metabolism
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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
SarcosineCitrullineOrnithine
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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
Ammonia Uric Acid Urea
Produced by Amino Acid Catabolism
Used in Urea CycleProduced by Purine
CatabolismProduced by Urea Cycle
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α-ketoglutarate Family
Transamination to Make Glutamate
α-ketoacid #1
Amino Acid #2
α-keto Acid #1 + Amino Acid X
Amino Acid #1 + α-keto Acid X
Amino Acid X
α-ketoacid X
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Glucose-Alanine Cycle
Alanine Metabolism
Glucose-Alanine Cycle Important for Removing Ammonia
High Ammonia Low Ammonia
Transamination in Liver Creates Glutamate
Alanine Carries Amine to Liver
Breakdown of Glutamate Yields Amine for Urea Production
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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
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Urea Cycle
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Carbamoyl Phosphate Synthetase Reaction
2 ATP + HCO3− + NH4+ <=> 2 ADP + Carbamoyl phosphate + P
The Source of Ammonium Ion is Glutamine or Glutamate Requires Action of Glutaminase (Glutamine) or Glutamate Dehydrogenase (Glutamate)
Glutamine + H2O
Glutamate + NH3
Glutamate + H2O + NADP+
α-ketoglutarate + NH3 + NADH + H+
H2O + CO2
HCO3- + NH4+
H2O + CO2
HCO3- + NH4+
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Ornithine Transcarbamoylase Reaction
+
Carbamoyl Phosphate
Ornithine
+Pi
Citrulline
Phosphate
Ornithine Transcarbamoylase
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
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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
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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
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Argininosuccinate Lyase
+
Argininosuccinic Acid Arginine Fumaric Acid
Bond Cleaved
Important for Production of Arginine Source of Fumarate Deficiency Like That of Other Urea Cycle Enzymes - Ammonia Excess
Argininosuccinate Lyase
Argininosuccinate Lyase
To Proteins or Remainder of Urea Cycle To Citric Acid Cycle
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Arginase
+ H2O +Arginine Urea Ornithine
CutExcreted
To Mitochondria To Complete Cycle Through
Ornithine Citrulline Translocase
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
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Urea Cycle
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Citrulline
Alternate Means of Producing Citrulline - Nitric Oxide Synthase Bypasses Mitochondrial Part of Urea Cycle & Produces Nitric Oxide Arginine is Substrate for Reaction
Nitric Oxide Important Signaling Molecule in Humans - Vasodilation
2 L-arginine + 3 NADPH + 1 H+ + 4 O2
2 Citrulline +2 Nitric Oxide + 4 H2O + 3 NADP+
Nitric Oxide Synthase
Viagra works by enhancing signaling through the nitric oxide pathway in the penis
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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
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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
Nitrosamine
NO+ + →H
Secondary Amine
Nitrite
H2NO2+ → H2O + NO+
Nitrosonium Ion
2H+
Nitrous Acid Ion
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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)
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Reactive Nitrogen Species
Reactive Nitrogen Species Can Arise from any of the Molecules Described Here The Most Potent Reactive Nitrogen Species is Peroxynitrite
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Reactive Nitrogen SpeciesPeroxynitrite 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·− ONOO−
Nitric OxideSuperoxide
Peroxynitrite
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Amino Acid Metabolism
IntroductionThere 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
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α-ketoglutarate Family
Transamination Plays an Important Roleα-keto Acid #1 + Amino Acid X
Amino Acid #1 + α-keto Acid X
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α-ketoglutarate Family
Transamination to Make Glutamate
α-ketoacid #1
Amino Acid #2
α-keto Acid #1 + Amino Acid X
Amino Acid #1 + α-keto Acid X
Amino Acid X
α-ketoacid X
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α-ketoglutarate Family
Glutamine Synthesis Uses Glutamine Synthetase
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α-ketoglutarate Family - Arginine Synthesis
Four Pathways to Make it
Deficiency of the Enzyme Arginase Leads to the Genetic Disease of Argininemia - Accumulation of Arginine and NH4+ in the Blood
ADMAArginine
Arginine
Citrulline + AspartateATP
ArgininosuccinateAMP + 2 Pi
Ornithine + Urea
H2O
Citrulline + Nitric Oxide + H2O
NADP+ NADPH + O2
DemythlationADMA
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Serine Family
3-PG + NAD+
3-phosphohydroxypyruvate
O-phosphoserine
Serine + Pi
H2O
Two Main Paths Lead to Serine
1. From 3-phosphoglycerate (Connection to Glycolysis)
Glutamateα-ketoglutarate
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Serine Family
2. Exchanging Carbon with Glycine and Folates (Important for Folate Recycling)
Serine + Tetrahydrofolate
Glycine + N5,N10-Methylene Tetrahydrofolate + H2O
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Serine Family
Cysteine Metabolism Multiple Ways of Making Cysteine Primary Means Tied to Methionine Catabolism
Methionine
SAM
SAH
Homocysteine
Cystathionine
Cysteine
Serine
ATPPi + PPi
AcceptorCH3-Acceptor
Adenosine H2O
β-ketobutyrate
Transmethylase
S-adenosylhomocysteine Hydrolase
Cystathionine β-synthase
Methionine Adenosyltransferase.
Cystathionase
Deficiency Leads to Homocystinuria
High Blood Levels - Cardiovascular Disease, Stroke Risk
H2ONH4+
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Serine Family
O-acetyl-L-serine
Acetyl-CoACoA-SH
L-cysteine + Acetate
H2S2 Cysteine
2 NADH + 2H+
2 NAD+
Serine L-cystine L-cysteic Acid
L-cysteine
H2SSulfite
Other Cysteine Metabolism
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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 SERtRNA
Non-SER tRNA
SEL-A SEL-DSELtRNA
Incorporation Into Proteins
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AspartateFamily
All Family Members Arise from Aspartate Aspartate Can be Made from One of Them - Asparagine Numerous Paths Lead to Aspartate
Asparagine + H2OGlutamate + Oxaloacetate Argininosuccinate + AMP
α-ketoglutarate + Aspartate Aspartate + NH4+ Aspartate + Citrullyl-AMP
Transamination Hydrolysis
Reversal ofReaction
Toxic
Urea Cycle
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Aspartate Family
Asparagine Metabolism
Aspartate + Glutamate + ATP
Asparagine + α-ketoglutarate + AMP + PPi
Energetically Costly Essentially Not Reversible
Asparagine Synthetase
Synthesis Breakdown
Asparagine + H2O
Aspartate + NH4+
Toxic
Asparaginase
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Aromatic Family Outline
Tryptophan Melatonin Serotonin Niacin Auxins
Phenylalanine Phenylketonuria
Tyrosine Catecholamines Thyroid Hormones Melanin
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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
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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
Serotonin Neurotransmitter Causes Vasoconstriction Enhances Memory/Learning, Contributor to Happy Feelings
Niacin Vitamin B3 Nicotinamide Derived From it - Part of NAD+/NADH & NADP+/NADPH Deficiency Leads to Pellagra
Auxins Indole-3-Acetic Acid Most Important Stimulate Cell Division and Rooting in Plants
Melatonin
Serotonin
Indole-3-Acetic Acid
Niacin
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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
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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
CO2
L-Norepinephrine
L-Norepinephrine
L-Ephinephrine
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Aromatic FamilyTyrosine 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
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Aromatic Family
Tyrosine is a Precursor of Thyroid Hormones
Secretion of Thyroglobulin
Export from Cell
Iodide Export& Oxidation
Iodination
Transport Into Cell
Thyroglobulin Breakdown
Transport Into Blood
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Aromatic Family
Tyrosine Metabolism
Thyroid Hormones
T3 (Triiodothyronine) T4 (Thyroxine)
Deiodinases
All are Se-Containing Enzymes
More Active Form More Abundant Form
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Aromatic Family
Tyrosine Metabolism
Melanin - Oxidized and Polymerized Tyrosine Benzoquinone Portion of Coenzyme Q
Tyrosine Unit
Further Polymerization
From Tyrosine
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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
p-hydroxyphenylpyruvate
Homogentisate
4-Maleylacetoacetate
4-Fumarylacetoacetate
Fumarate + Acetoacetate
Tyrosine TransaminaseType II
p-hydroxyphenylpyruvate DioxygenaseType III
AlcaptonuriaAlcaptonuria
4-fumarylacetoacetaseType I
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Pyruvate FamilyAlanine Metabolism
Most Easily Produced from Pyruvate - Transamination Byproduct of Catabolism of Valine, Leucine, and Isoleucine Glucose-Alanine Cycle
Alanine Transaminase
Glutamate + Pyruvate
α-ketoglutarate + Alanine
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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-β-methylvalerate (ILE) Each is Transaminated to Make Final Amino Acid
Isoleucine Leucine Valine
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Pyruvate Family
Leucine (LEU) /Valine (VAL) /Isoleucine (ILE) Metabolism
Synthesis Feedback Regulated Through Threonine Deaminase
Starting Material for ILE
Starting Material for VAL & LEUMakes Starting Material for ILE
Used by All Three
High ILE Favors VAL & LEU
High VAL Favors ILE
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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
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Amino Acid Catabolism
GlycogenicAlanine, Cysteine, Glycine, Serine Asparagine, Aspartate, Arginine Histidine, Proline, Glutamine Glutamate, Methionine, Valine
KetogenicLysine, Leucine
BothThreonine,Tryptophan, Tyrosine, Phenylalanine, Isoleucine
Three Categories 1. Glycogenic - Broken Down to Glycolysis/Gluconeogenesis Intermediates 2. Ketogenic - Broken Down to Acetyl-CoA 3. Both - Makes Intermediates in Both Pathways
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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