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Nitrogen Metabolism Dr. Kevin Ahern Nitrogen Metabolism Dr. Kevin Ahern

Nitrogen Metabolism Dr. Kevin Ahern - PowerPoint Presentation

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Nitrogen Metabolism Dr. Kevin Ahern - PPT Presentation

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 ID: 659770

family acid cycle amino acid family amino cycle tyrosine metabolism urea amp aspartate nitrogen citrulline nitric oxide serine glutamate

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Slide1

Nitrogen Metabolism

Dr. Kevin AhernSlide2

Nitrogen MetabolismSlide3

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 AcidsOrnithineCitrullineSarcosineOther Nitrogen-Containing CompoundsCholineVitaminsCarnitine

Sarcosine

Citrulline

OrnithineSlide4

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 - BirdsUreotelic - Excrete Urea - Most Vertebrates, Some Invertebrates

Ammonia

Uric Acid

Urea

Produced by Amino

Acid Catabolism

Used in Urea Cycle

Produced by Purine

Catabolism

Produced by

Urea CycleSlide5

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 XSlide6

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 ProductionSlide7
Slide8

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 CO

2

Per TurnCycle Reaction Provides 1 Amine from an Amino AcidOutput of Cycle is 1 Molecule of Urea Per TurnThe Net Reaction Per Turn of the Cycle is 2 NH3 + CO2 + 3 ATP + H2O → urea + 2 ADP + 4 Pi + AMPSlide9

Urea CycleSlide10

Carbamoyl Phosphate Synthetase Reaction

2 ATP + HCO

3

+ NH

4+ <=> 2 ADP + Carbamoyl phosphate + PThe Source of Ammonium Ion is Glutamine or GlutamateRequires Action of Glutaminase (Glutamine) or Glutamate Dehydrogenase (Glutamate)

Glutamine + H

2O

Glutamate + NH3

Glutamate + H

2

O + NADP

+

α-ketoglutarate + NH

3

+ NADH + H

+

H

2

O + CO

2

HCO

3

-

+ NH

4

+

H

2

O + CO

2

HCO

3

-

+ NH

4

+Slide11

Ornithine Transcarbamoylase Reaction

+

Carbamoyl Phosphate

Ornithine

+

P

i

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 TreatmentsSlide12

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 OnsetSlide13

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 CycleGene Expression of Enzyme Reduced by Arginine, Increased by CitrullineEnzyme Defects Lead to Citrullinemia - Accumulation of AmmoniaTreated with Low Protein Diet, Arginine Supplementation

1

2Slide14

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 CycleSlide15

Arginase

+

H

2

O

+

Arginine

Urea

Ornithine

Cut

Excreted

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 DeficientSlide16

Urea CycleSlide17

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 H

2O + 3 NADP+

Nitric Oxide Synthase

Viagra works by enhancing signaling through the nitric oxide pathway in the penisSlide18

Nitrites

Nitrite formed by Ionization of Nitrous Acid (HNO

2

) or Reduction of Nitrates

Nitrite Used to Cure Meats and Prevent Botulism

Can Be Reduced to Nitric Oxide in Hypoxic ConditionsIn Human Diet 80-90% from Reduction of Nitrates in VegetablesNitrates in Vegetables From Fertilizers or Plant StressesNitrite 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 SeriousSlide19

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

H

2

NO

2

+

→ H

2

O + NO

+

Nitrosonium Ion

2H

+

Nitrous Acid IonSlide20

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-cigarettesNNK Activation by P-450 Activated Signaling Cascades & Uncontrolled Growth

Nicotine-derived nitrosamine ketone (NNK)

(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)Slide21

Reactive Nitrogen Species

Reactive Nitrogen Species Can Arise from any of the Molecules Described Here

The Most Potent Reactive Nitrogen Species is PeroxynitriteSlide22

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 + O

2·− ONOO

Nitric Oxide

Superoxide

PeroxynitriteSlide23

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-ketoglutarateSerineAspartateAromatic

PyruvateHistidine

Essential Amino Acids Must Be in DietNon-Essential Ones Can be Made by OrganismEssential vs Non-Essential Varies in HumansSlide24

α-ketoglutarate Family

Transamination Plays an Important Role

α-keto Acid #1 +

Amino Acid X

Amino Acid #1

+ α-keto Acid XSlide25

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 XSlide26

α-ketoglutarate Family

Glutamine Synthesis Uses Glutamine SynthetaseSlide27

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 NH

4

+

in the Blood

ADMA

Arginine

Arginine

Citrulline + Aspartate

ATP

Argininosuccinate

AMP + 2 P

i

Ornithine + Urea

H

2

O

Citrulline + Nitric Oxide + H

2

O

NADP

+

NADPH + O

2

Demythlation

ADMASlide28

Serine Family

3-PG + NAD

+

3-phosphohydroxypyruvate

O-phosphoserine

Serine + P

i

H

2

O

Two Main Paths Lead to Serine

1. From 3-phosphoglycerate

(Connection to Glycolysis)

Glutamate

α-ketoglutarateSlide29

Serine Family

2. Exchanging Carbon with Glycine and Folates

(Important for Folate Recycling)

Serine + Tetrahydrofolate

Glycine + N

5

,N

10

-Methylene Tetrahydrofolate + H

2

OSlide30

Serine Family

Cysteine Metabolism

Multiple Ways of Making Cysteine

Primary Means Tied to Methionine Catabolism

Methionine

SAM

SAH

Homocysteine

Cystathionine

Cysteine

Serine

ATP

P

i

+ PP

i

Acceptor

CH

3

-Acceptor

Adenosine

H

2

O

β-ketobutyrate

Transmethylase

S-adenosylhomocysteine Hydrolase

Cystathionine β-synthase

Methionine Adenosyltransferase.

Cystathionase

Deficiency Leads to Homocystinuria

High Blood Levels - Cardiovascular Disease, Stroke Risk

H

2

O

NH

4

+Slide31

Serine Family

O-acetyl-L-serine

Acetyl-CoA

CoA-SH

L-cysteine + Acetate

H

2

S

2 Cysteine

2 NADH + 2H

+

2 NAD

+

Serine

L-cystine

L-cysteic Acid

L-cysteine

H

2

S

Sulfite

Other Cysteine MetabolismSlide32

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 tRNASerine + tRNA

SER

tRNA

Non-SER tRNA

SEL-A

SEL-D

SEL

tRNA

Incorporation Into ProteinsSlide33

Aspartate Family

All Family Members Arise from Aspartate

Aspartate Can be Made from One of Them - Asparagine

Numerous Paths Lead to Aspartate

Asparagine + H

2

O

Glutamate + Oxaloacetate

Argininosuccinate + AMP

α-ketoglutarate + Aspartate

Aspartate + NH

4

+

Aspartate + Citrullyl-AMP

Transamination

Hydrolysis

Reversal of

Reaction

Toxic

Urea CycleSlide34

Aspartate Family

Asparagine Metabolism

Aspartate + Glutamate + ATP

Asparagine + α-ketoglutarate + AMP + PP

i

Energetically Costly

Essentially Not Reversible

Asparagine Synthetase

Synthesis

Breakdown

Asparagine + H

2

O

Aspartate + NH

4

+

Toxic

AsparaginaseSlide35

Aromatic Family Outline

Tryptophan

Melatonin

Serotonin

Niacin

AuxinsPhenylalaninePhenylketonuriaTyrosineCatecholaminesThyroid Hormones

MelaninSlide36

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 OverlapHormones and Neurotransmitters Made from EachSlide37

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 GenesMolecules Made from TryptophanMelatoninCircadian Rhythm SensingAffects Mood, Sleep, Blood Pressure

Production Affected by Blue LightSerotonin

NeurotransmitterCauses Vasoconstriction

Enhances Memory/Learning, Contributor to Happy FeelingsNiacinVitamin B3Nicotinamide Derived From it - Part of NAD+/NADH & NADP+/NADPH

Deficiency Leads to Pellagra

AuxinsIndole-3-Acetic Acid Most ImportantStimulate Cell Division and Rooting in Plants

Melatonin

Serotonin

Indole-3-Acetic Acid

NiacinSlide38

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 BrainTreatable by Reducing PHE LevelsNutrasweet Contains PHESlide39

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

CO

2

L-Norepinephrine

L-Norepinephrine

L-EphinephrineSlide40

Aromatic Family

Tyrosine Metabolism

L-Dopa

Precursor to Dopamine

Crosses Blood-Brain Barrier

Used to Treat Parkinson’s DiseaseDopamineNeurotransmitterInhibits Norepinephrine Release in Blood Vessels - Acts as VasodilatorReduces Insulin Production in PancreasDeficiency Causes Parkinson’s DiseaseLinks to Schizophrenia and ADHD

Norepinephrine

Hormone and NeurotransmitterWorks Through Noradrenergic ReceptorsFight or Flight Response

Increases Heart Rate and Blood PressureEpinephrine (Adrenalin)HormoneActions Similar to Norepinephrine

Fight or Flight ResponseIncreases Heart Rate and Blood PressureSlide41

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 BloodSlide42

Aromatic Family

Tyrosine Metabolism

Thyroid Hormones

T3 (Triiodothyronine)

T4 (Thyroxine)

Deiodinases

All are Se-Containing Enzymes

More Active Form

More Abundant FormSlide43

Aromatic Family

Tyrosine Metabolism

Melanin - Oxidized and Polymerized Tyrosine

Benzoquinone Portion of Coenzyme Q

Tyrosine Unit

Further Polymerization

From TyrosineSlide44

Aromatic Family

Tyrosine Metabolism & Disease

Tyrosinemia - Problems with Tyrosine Catabolism

Type I

Type II

Type IIIAlcaptonuria - Black Urine DiseaseTreatmentsRestricted TYR/PHE DietLiver Transplant

Tyrosine

p-hydroxyphenylpyruvate

Homogentisate

4-Maleylacetoacetate

4-Fumarylacetoacetate

Fumarate + Acetoacetate

Tyrosine Transaminase

Type II

p-hydroxyphenylpyruvate Dioxygenase

Type III

Alcaptonuria

Alcaptonuria

4-fumarylacetoacetase

Type ISlide45

Pyruvate Family

Alanine Metabolism

Most Easily Produced from Pyruvate - Transamination

Byproduct of Catabolism of Valine, Leucine, and Isoleucine

Glucose-Alanine Cycle

Alanine Transaminase

Glutamate + Pyruvate

α-ketoglutarate + AlanineSlide46

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 PyruvateIsoleucine Pathway Involves Attaching Two Carbon Piece to α-ketobutyratePenultimate Products - α-ketoisocaproate (LEU), α-ketoisovalerate (VAL), and α-keto-β-methylvalerate (ILE) Each is Transaminated to Make Final Amino Acid

Isoleucine

Leucine

ValineSlide47

Pyruvate Family

Leucine (LEU) /Valine (VAL) /Isoleucine (ILE) Metabolism

Synthesis Feedback Regulated Through Threonine Deaminase

Starting Material for ILE

Starting Material for VAL & LEU

Makes Starting

Material for ILE

Used by

All Three

High ILE

Favors VAL & LEU

High VAL

Favors ILESlide48

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

HistidineSlide49

Amino Acid Catabolism

Glycogenic

Alanine, Cysteine, Glycine, Serine

Asparagine, Aspartate, Arginine

Histidine, Proline, Glutamine

Glutamate, Methionine, ValineKetogenicLysine, LeucineBoth

Threonine,Tryptophan, Tyrosine,

Phenylalanine, Isoleucine

Three Categories1. Glycogenic - Broken Down to Glycolysis/Gluconeogenesis Intermediates

2.

Ketogenic - Broken Down to Acetyl-CoA3. Both - Makes Intermediates in Both PathwaysSlide50

Amino Acid Catabolism

Most Diseases of Amino Acid Metabolism Arise from Problems with Catabolism

Alcaptonuria - Phenylalanine and Tyrosine

Methylmalonic Acidemia - Methionine

, T

hreonine, Isoleucine and ValineMaple Syrup Urine Disease - Valine, Leucine, IsoleucineHomocystinuria - MethionineTyrosinemia - TyrosineArgininemia - ArginineHypermethioninemia - MethionineHyperlysinemia - Lysine

Glycine Encephalopathy - Glycine

Propionic Acidemia - Methionine, Threonine, Isoleucine and

ValineHyperprolinemia - Proline