AMINO ACID BIOSYNTHESIS

NON-ESSENTIAL AMINO ACIDS ESSENTIAL AMINO ACIDS SINGLE CARBON TRANSFERS WITH THF PHYSIOLOGIC AMINES

AMINO ACID BIOSYNTHESIS

FIXING OF ATMOSPHERIC N2

DIAZOTROPHS FIX N2 TO NH3 IN MICRO-ORGANISMS, PLANTS, LOWER ANIMALS:

GLU

DEHYDROGENASE RXN

GLU + NAD(P)+ + H2O -KG + NH3 + NAD(P)H + H+ REVERSE RXN GLU

GLU

SYNTHASE RXN GLU

NADPH + H+ + GLN + -KG 2 GLU + NADP+

AMINO ACID BIOSYNTHESIS

DOES THE GLU DEHYDROGENASE RXN WORK IN

REVERSE IN MAMMALS?

THERE IS SOME CONTROVERSY ABOUT THIS THE HYPERAMMONEMIA/HYPERINSULINEMIA SYNDROME (HI/HA) IS CAUSED BY A MUTATION IN GDH THAT A GAIN IN FUNCTION

SUGGESTS THAT THE PREFERRED DIRECTION IS TOWARD THE RIGHT

DEPENDING UPON THE ORGANISM, THE GLU DEHYDROGENASE MIGHT BE CLOSE TO EQUILIBRIUM, OR FAVORED TO THE RIGHT OR LEFT

SO, PREFORMED -AMINO NITROGEN, IN THE FORM

OF GLU, MUST BE CONSIDERED AN ESSENTIAL NUTRIENT

AMINO ACID BIOSYNTHESIS

ESSENTIAL AMINO ACIDS

*ARGININE HISTIDINE ISOLEUCINE LEUCINE LYSINE

NOTE

METHIONINE PHENYLALANINE THREONINE TRYPTOPHAN VALINE

ARG IS ESSENTIAL IN INFANTS AND CHILDREN MOST SYNTHESIZED ARG ORNITHINE AND UREA VIA THE UREA CYCLE

AMINO ACID BIOSYNTHESIS

NONESSENTIAL AMINO ACIDS

ALANINE ASPARAGINE ASPARTATE *CYSTEINE GLUTAMATE

GLUTAMINE GLYCINE PROLINE SERINE *TYROSINE

NOTE: CYS GETS ITS SULFUR ATOM FROM MET TYR IS HYDROXYLATED PHE SO ITS NOT REALLY NONESSENTIAL

AMINO ACID BIOSYNTHESIS

ALL ARE SYNTHESIZED FROM COMMON METABOLIC

INTERMEDIATES NON-ESSENTIAL

TRANSAMINATION OF -KETOACIDS THAT ARE AVAILABLE AS COMMON INTERMEDIATES THEIR -KETOACIDS ARE NOT COMMON INTERMEDIATES (ENZYMES NEEDED TO FORM THEM ARE LACKING)

ESSENTIAL

SO TRANSAMINATION ISNT AN OPTION

BUT THEY ARE PRESENT IN COMMON PATHWAYS OF MICRO-ORGANISMS AND PLANTS

AMINO ACID BIOSYNTHESIS OVERVIEW (USE OF COMMON INTERMEDIATES)

GLUCOSE GLUC-6-PHOSPHATE RIB-5-PHOS HIS 3-PHOSPHOGLYCERATE SERINE GLYCINE E-4-PHOS + PEP CYSTEINE PHETYR PYRUVATE ALA TRP VAL CITRATE LEU, ILE OXALOACETATE, -KETOGLUTARATE ASP, ASN, GLU, GLN, PRO, ARG, LYS, THR, MET

SYNTHESIS OF NON-ESSENTIAL AMINO ACIDS

ALL (EXCEPT TYR) SYNTHESIZED

FROM COMMON INTERMEDIATES SYNTHESIZED IN CELL

PYRUVATE OXALOACETATE -KETOGLUTARATE 3-PHOSPHOGLYCERATE

SYNTHESIS OF NON-ESSENTIAL AMINO ACIDS

TRANSAMINATION REACTIONS: ONE STEP

PYRUVATE + AA ALANINE + -KETOACID OXALOACETATE + AA ASPARTATE + KETOACID -KETOGLUTARATE + AA GLUTAMATE + KETOACID REQUIRE PYRIDOXAL PHOSPHATE (PLP) ALL AAs, EXCEPT LYS, CAN BE TRANSAMINATED MOST TRANSAMINASES GENERATE GLU OR ASP

TRANSAMINASES: EQUILIBRATE AMINO GROUPS

WHY?

LOOK AT MECHANISM OF PLP (PAGE 987 IN TEXT)

A C B

SYNTHESIS OF NONESSENTIAL AMINO ACIDS

ATP-DEPENDENT AMIDATION OF ASP, GLU

ASN, GLN GLU + ATP + NH3 GLN + ADP + Pi

GLUTAMINE SYNTHETASE NH IS TOXIC; ITS STORED AS GLN 3

GLN DONATES AMINO GPS IN MANY REACTIONS

ASP + ATP + GLN ASN + AMP + PPi + GLU ASPARAGINE SYNTHETASE

SYNTHESIS OF NONESSENTIAL AMINO ACIDS

NITROGEN METABOLISM IS CONTROLLED BY

REGULATION OF GLUTAMINE SYNTHETASE

IN MAMMALS, GLN SYNTHETASES ACTIVATED BY -KG EXCESS AAs TRANSAMINATED TO GLU OXIDATIVE DEAMINATION OF GLU -KG + NH3 NH 3 UREA OR GLN (STORAGE)

-KG IS A SIGNAL THAT ACTIVATES GLN

SYNTHETASE

BACTERIAL GLUTAMINE SYNTHETASE

VERY DETAILED CONTROL SYSTEM 12 IDENTICAL SUBUNITS (HEX PRISM)

ALLOSTERIC CONTROL 9 FEEDBACK INHIBITORS (CUMULATIVE INH) INDIVIDUAL BINDING SITES 6 ARE END-PRODS OF PATHWAYS FROM GLN HIS, TRP, CARBAMOYL PHOSPHATE, AMP, CTP, GLUCOSAMINE-6-PHOSPHATE 3 REFLECT CELLS N LEVEL (ALA, SER, GLY)

ALSO COVALENTLY MODIFIED BY

ADENYLYLATION

BACTERIAL GLUTAMINE SYNTHETASE

BRIEF REVIEW: REGULATING ENZYME

ACTIVITY

NEAR-EQUILIBRIUM (REVERSIBLE)
REACTANTS, PRODUCTS ~ EQUIL. VALUES ENZYMES ACT QUICKLY TO RESTORE EQUIL. RATES REGULATED BY [REACT], [PROD] ENZYME SATURATED NOT ENOUGH ACTIVITY TO ALLOW EQUIL. RATE INSENSITIVE TO [REACT], [PROD] STEADY STATE (CONSTANT FLUX) RATE-DETERMINING STEP

FAR FROM EQUILIBRIUM (IRREVERSIBLE)

BACTERIAL GLUTAMINE SYNTHETASE

BRIEF REVIEW: REGULATING ENZYME

ACTIVITY

CONTROL OF ENZYME ACTIVITY

ALLOSTERIC REGULATION COVALENT MODIFICATION GENETIC CONTROL

AT LEVEL OF TRANSCRIPTION

BACTERIAL GLUTAMINE SYNTHETASE

SEE REGULATORY DIAGRAM (PAGE 1035) ADENYLYLATION OF A SPECIFIC TYR RESIDUE LESS ACTIVITY OF THE ENZYME ENZYME IS ADENYLYLTRANSFERASE IN A COMPLEX WITH A TETRAMERIC REGULATORY PROTEIN, PII

URIDYLYLATION OF PII (AT A TYR) DEADENYLYLATION A URIDYL-REMOVING ENZYME RESULTS IN ADENYLYLTRANSFERASE CATALYZING ADENYLYLATION OF GLN SYNTHETASE

BACTERIAL GLUTAMINE SYNTHETASE

SEE REGULATORY DIAGRAM (PAGE 1035)

WHAT CONTROLS ACTIVITY OF URIDYLYL

TRANSFERASE? ACTIVATED BY -KG AND ATP DEACTIVATED BY GLN AND P i TO THESE

URIDYL-REMOVING ENZYME INSENSITIVE

Bacterial Glutamine Synthetase Regulation

(Less Active)

O O P O O CH2 H H HO O H H OH Adenine

Uridylyltransferase -Ketoglutarate ATP Glutamine X Pi X

Adenylyltransferase

Adenylyltransferase

PPi
PII

PII

UTP

PPi

Pi

ATP
O

O P O O

OH

UMP

H2O

CH2 H H HO O H

Uracil H OH

ADP

Uridylyl-removing Enzyme
Glutamine Synthetase

BACTERIAL GLUTAMINE SYNTHETASE

IN-CLASS EXERCISE

EXPLAIN THE SIGNIFICANCE OF -KG AS AN ACTIVATOR OF GLUTAMINE SYNTHETASE SHOW, IN DETAIL, THE EFFECT OF LEVEL OF -KG ON THIS ENZYME. DO THE SAME FOR ATP, GLN AND Pi

NONESSENTIAL AMINO ACID SYNTHESIS

PRO, ORNITHINE, ARG ARE DERIVED FROM GLUTAMATE

NOTE: 7 OF THE 10 NONESSENTIALS ARE ULTIMATELY DERIVED FROM PYR, -KG AND OXALOACETATE

SEE PATHWAYS ON PAGE 1036 HIGHLIGHTS:

STEP 1: ACTIVATE GLU; A KINASE GLUTAMATE-5-SEMIALDEHYDE BRANCH POINT

SPONTANEOUS CYCLIZATION TO AN INTERNAL SCHIFF BASE PRO TRANSAMINATION TO ORNITHINE ARG IN UREA CYCLE

SCHIFF BASE: AMINE + (ALDEHYDE OR KETONE)

IMINE (CONTAINS A C=N BOND)

NONESSENTIAL AMINO ACID SYNTHESIS

3-PHOSPHOGLYCERATE IS PRECURSOR OF

SER (A 3-STEP PATHWAY) (1) 3-PG + NAD+ 3-PHOSPHOHYDROXYPYRUVATE + NADH + H+ (2) 3-PHP + GLU 3-PHOSPHOSERINE + -KG (3) 3-PHOSPHOSERINE + H2O SER + Pi

GLY (2 DIFFERENT WAYS) (1) SER + THF GLY + N5,N10 METHYLENE-THF (DIRECT) (2) N5,N10 METHYLENE-THF + CO2 + NH4+ GLY + THF (CONDENSATION)

NONESSENTIAL AMINO ACID SYNTHESIS

CYSTEINE

SER + HOMOCYSTEINE CYSTATHIONINE

HOMOCYSTEINE

IS A BREAKDOWN PRODUCT OF METHIONINE

CYSTATHIONINE -KETOBUTYRATE + CYS NOTE: -SH GROUP COMES FROM MET

SO CYS IS ACTUALLY AN ESSENTIAL AMINO ACID

NONESSENTIAL AMINO ACID SYNTHESIS

SUMMARY POINT:

ALL NONESSENTIALS (EXCEPT TYR) ARE DERIVED FROM ONE OF THE FOLLOWING COMMON INTERMEDIATES:
PYRUVATE OXALOACETATE -KG 3-PHOSPHOGLYCERATE

IN-CLASS EXERCISE

WHICH OF THE 4 AMINO ACID INTERMEDIATES OF THE

UREA CYCLE IS ESSENTIAL IN CHILDREN?

OUTLINE A PATHWAY BY WHICH ADULTS CAN

SYNTHESIZE THIS AA FROM 1 GLUCOSE MOLECULE. HINTS: YOU WILL NEED TO CONSIDER THE FOLLOWING METABOLIC PATHWAYS: GLYCOLYTIC GLUCONEOGENIC CITRIC ACID CYCLE GLUTAMATE DEHYDROGENASE REACTION

ASSUME IT CAN GO IN REVERSE DIRECTION

ORNITHINE PRODUCTION UREA CYCLE

TRANSFER OF C1 UNITS TO METABOLIC PRECURSORS

MOST CARBOXYLATION REACTIONS USE A

BIOTIN COFACTOR

EXAMPLE: PYRUVATE CARBOXYLASE REACTION

S-ADENOSYLMETHIONINE (SAM) AS A

METHYLATING AGENT

CYTOSINE METHYLATION OF CpGs IN GENE PROMOTER REGIONS

TETRAHYDROFOLATES CAN TRANSFER SINGLE C UNITS IN A NUMBER OF DIFFERENT OXIDATION STATES

TETRAHYDROFOLATES
REVIEW STRUCTURE (PAGE 1028 OF TEXT) FOCUS ON HETEROCYCLIC RING STRUCTURE 2-AMINO-4-OXO-6-METHYLPTERIN NOTICE THE NUMBERING OF THE ATOMS LOOK AT N5 PABA JOINS TO 2-AMINO-4-OXO-6METHYLPTERIN TO FORM PTEROIC ACID FIND N10 COVALENT ATTACHMENT OF C1 UNITS AT

N5 N10 BOTH

TETRAHYDROFOLATE
THREE DIFFERENT OXIDATION STATES

METHANOL

AT N5

METHYL (-CH3) METHYLENE (-CH2-) FORMYL (-CH=O) FORMIMINO (-CH=NH) METHENYL ( -CH=) AT N5 OR N10 AT N5 AT N5,N10

FORMALDEHYDE AT N5,N10

FORMATE

LOOK AGAIN AT THE 2 REACTIONS FOR SYNTHESIS OF

GLY

SERINE HYDROXYMETHYLTRANSFERASE GLYCINE SYNTHASE

THF IS INVOLVED IN EACH

TETRAHYDROFOLATE
C1 UNITS ENTER THE THF POOL MAINLY

FROM THESE TWO REACTIONS

AS N5,N10 METHYLENE-THF

OXIDATION STATES OF C1 UNITS ATTACHED TO THF ARE INTERCONVERTIBLE

VIA ENZYMATIC REDOX REACTIONS

WE WILL SEE THF AGAIN METHIONINE SYNTHESIS HIS SYNTHESIS PURINE SYNTHESIS dTMP (THYMIDYLATE) SYNTHESIS

TETRAHYDROFOLATE
THF IS DERIVED FROM FOLIC ACID

MAMMALS CANNOT SYNTHESIZE IT DEFICIENCY DURING EARLY PREGNANCY CAN LEAD TO NEURAL TUBE DEFECTS ANENCEPHALY SPINA BIFIDA SULFONAMIDES COMPETITIVELY INHIBIT STRUCTURAL ANALOGS OF PABA GOOD ANTIBACTERIAL AGENTS WHY ARE MAMMALS UNAFFECTED?

BACTERIA SYNTHESIZE FOLIC ACID

TETRAHYDROFOLATE
STUDY QUESTION: IF I GIVE YOU THE

STRUCTURE OF THF, NUMBERING THE ATOMS ACCORDINGLY, BE ABLE TO SHOW WHERE TO ATTACH THE 5 DIFFERENT C1 GROUPS.

TRANSAMINATION REACTIONS
IN-CLASS STUDY QUESTION
DRAW THE STRUCTURES OF THE KETO-

ACID PRODUCTS OF THE REACTIONS OF THE FOLLOWING AMINO ACIDS WITH -KG.

GLY ARG SER

DRAW THE STRUCTURE OF THE AMINO

ACID PRODUCT COMMON TO ALL 3 RXNS

REFERENCES
HERE ARE TWO ARTICLES THAT MIGHT

HELP YOU TO ORGANIZE YOUR THINKING ABOUT AMINO ACID METABOLISM:

(1) Glutamate and Glutamine, at the Interface between Amino Acid and Carbohydrate Metabolism (Brosnan JT, The Journal of Nutrition, Apr 2000, 130,4S: 988S 990S) (2) Disorders of Glutamate Metabolism (Kelly A, Stanley CA, 2001. Mental Retardation and Developmental Disabilities Research Reviews, 7:287-295

SYNTHESIS OF ESSENTIAL AMINO ACIDS

ALL SYNTHESIZED FROM COMMON METABOLIC

PRECURSORS

ASPARTATE PYRUVATE PHOSPHOENOLPYRUVATE ERYTHROSE-4-PHOSPHATE PURINE + ATP (HISTIDINE) PROBABLE EVOLUTIONARY LOSS IN MAMMALS PATHWAYS ARE VERY COMPLICATED ACTUAL PATHWAYS VARY ACROSS SPECIES!

PATHWAYS ONLY IN MICRO-ORGANISMS AND

PLANTS

IN CONTRAST TO LIPID AND CARBOHYDRATE PATHWAYS, WHICH ARE ALMOST UNIVERSAL

ESSENTIAL AMINO ACID SYNTHESIS

FOUR FAMILIES ASPARTATE LYS MET THR PYRUVATE LEU, ILE, VAL (THE BRANCHED CHAIN AMINO ACIDS) AROMATIC PHE TYR TRP HISTIDINE

THE ASPARTATE FAMILY

FIRST COMMITTED STEP IS

ASP + ATP ASPARTYL-PHOSPHATE + ADP

ENZYME:

ASPARTOKINASE

3 ISOZYMES IN E.coli EACH RESPONDS DIFFERENTLY AS FAR AS FEEDBACK INHIBITION AND REPRESSION OF ENZYME SYNTHESIS

THR,LYS,

MET PATHWAYS INDEPENDENTLY CONTROLLED

THE ASPARTATE FAMILY

CONTROL OF ASPARTOKINASE ISOENZYMES

ENZYME FEEDBACK INHIB COREPRESSOR

ASP I ASP II ASP III

THR NONE LYS

THR, ILE MET LYS

COREPRESSOR: TRANSCRIPTIONAL REPRESSION

ASPARTATE FAMILY
ALSO CONTROL AT BRANCH POINTS NOTE THE FOLLOWING REACTION:

HOMOCYSTEINE + N5-METHYL-THF MET + THF

HOMOCYSTEINE CV DISEASE RISK FACTOR EAT FOODS CONTAINING FOLATE RECALL:SER + HOMOCYSTEINE CYSTATHIONINE ENZYME DEFECTS IN REMETHYLATION OF HOMOCYSTEINE TO MET OR IN RXN FROM CYSTATHIONINE CYS HOMOCYSTEINE DEFECT IN SYNTHESIS OF CYSTATHIONE--SYNTHASE

ENZYME: METHIONINE SYNTHASE (?)

HYPER HOMOCYSTENEMIA HOMOCYSTEINURIA SYMPTOMS:

PREMATURE ATHEROSCLEROSIS THROMBOEMBOLIC COMPLICATIONS SKELETAL ABNORMALITIES ECTOPIA LENTIS MENTAL RETARDATION

THE PYRUVATE FAMILY

BRANCHED CHAIN AMINO ACIDS

LEU ILE VAL

VAL, ILE: SAME PATHWAY AFTER 1st STEP LEU PATHWAY BRANCHES FROM VAL

PATHWAY FINAL STEPS ALL CATALYZED BY AMINOTRANSFERASES

GLU IS THE AMINO DONOR

THE PYRUVATE FAMILY

THE FIRST STEP:

PYR + TPP HYDROXYETHYL-TPP

FIRST

PYR AND TPP FORM AN ADDUCT THEN DECARBOXYLATED TO HE-TPP A RESONANCE-STABILIZED CARBANION

A STRONG NUCLEOPHILE ADDS TO KETO GROUP OF PYRUVATE VAL, LEU -KETOBUTYRATE ILE

THE PYRUVATE FAMILY

LOOK AT THE REACTION MECHANISM OF PYRUVATE

DECARBOXYLASE (PAGE 605)

THIS SHOWS THE FORMATION OF THE HYDROXYETHYL-TPP ADDUCT THIAMINE (VIT B1) THIAZOLIUM RING

SOME INTERESTING CHEMISTRY

ACIDIC HYDROGEN ELECTRON SINK

TRANSITION STATE STABILIZATION MECH. YLIDS RESONANCE

THE AROMATIC FAMILY

IN PLANTS AND MICRORGANISMS

PHE TYR TRP PEP ERYTHROSE-4-PHOSPHATE THESE CONDENSE WITH ULTIMATE CONVERSION TO CHORISMATE

PECURSORS ARE:

THE AROMATIC FAMILY

CHORISMATE

BRANCH POINT FOR TRP SYNTHESIS CHORISMATE ANTHRANILATE TRP CHORISMATE PREPHENATE BRANCH POINT FOR PHE, TYR SYNTH AMINOTRANSFERASES IN EACH FINAL STEP IN MAMMALS, TYR IS A PRODUCT OF: PHE HYDROXYLATION

PREPHENATE

THE TRP PATHWAY

TRYPTOPHAN SYNTHASE

CATALYZES FINAL 2 STEPS

INDOLE-3-GLYCEROL PHOS INDOLE + GLYC-3-P INDOLE + SER H2O + TRP

22 BIFUNCTIONAL ENZYME WHAT ENZYME CLASS?

THE TRP PATHWAY

CHANNELING

INDOLE IS SEQUESTERED BETWEEN THE TWO ACTIVE SITES DIFFUSES BETWEEN TWO SITES ITS NONPOLAR WHAT ARE THE BENEFITS OF CHANNELING?

STUDY QUESTION:

SEE RIBBON DIAGRAM OF TRP SYNTHASE

ON PAGE 1044

MECHANISM?

PHENYLKETONURIA (PKU)

DEFECTIVE OR ABSENT PHENYLALANINE

HYDROXYLASE CANNOT FORM TYROSINE PHE BUILDS UP PHE IS TRANSAMINATED TO PHENYL-PYRUVATE SEVERE MR IF NOT TREATED SOON AFTER BIRTH WITH LOW PHE DIET UNIVERSAL NEWBORN SCREENING

PHENYLKETONURIA
IN-CLASS STUDY QUESTION
WRITE OUT THE REACTION IN WHICH PHE IS

TRANSAMINATED TO PHENYLPYRUVATE, SHOWING STRUCTURES EXPLAIN WHY CHILDREN WITH A TETRAHYDROBIOPTERIN DEFICIENCY EXCRETE LARGE AMOUNTS OF PHE WHY DO PEOPLE WITH PKU HAVE BLOND HAIR, BLUE EYES AND VERY LIGHT SKIN? WHY DO PEOPLE ON A LOW PHE-DIET NEED TO INCREASE THEIR TYR INTAKE?

HISTIDINE BIOSYNTHESIS
ATOMS DERIVED FROM:

5-PHOSPHORIBOSYL--PYROPHOSPHATE
PROVIDES 5 C-ATOMS PRPP INVOLVED IN PURINE SYNTHESIS PRPP INVOLVED IN PYRIMIDINE SYNTHESIS PURINE SALVAGE PATHWAY AN INTERMEDIATE IN TRP SYNTHESIS

ATP PROVIDES THE 6th C-ATOM

ATP + -D-RIBOSE-5-PHOSPHATE PRPP +

AMP

-D-RIBOSE-5-PHOSPHATE FROM H-M SHUNT

HISTIDINE BIOSYNTHESIS
NOTICE THE PRODUCTS OF THE AMIDO-

TRANSFERASE STEP:

AICAR AN INTERMEDIATE IN PURINE BIOSYNTHESIS IMIDAZOLE GLYCEROL PHOSPHATE

THERE IS AN APPARENT EVOLUTIONARY

OVERLAP OF PURINE AND HIS SYNTHESIS

THE FIRST STEP IN HIS SYNTHESIS INVOLVES FORMATION OF A PURINE!

HISTIDINE BIOSYNTHESIS
IS THE HIS PATHWAY A RELIC OF THE

TRANSITION FROM RNA-BASED TO PROTEIN-BASED LIFE FORMS?

HIS IS FREQUENTLY FOUND IN ENZYME ACTIVE SITES

NUCLEOPHILES GENERAL ACID/BASE CATALYSIS

RNA HAS CATALYTIC PROPERTIES IMIDAZOLE GROUP PROBABLY PLAYS A SIMILAR ROLE

PHYSIOLOGICALLY ACTIVE AMINES

THESE ARE DERIVED FROM AMINO ACIDS THEY INCLUDE

EPINEPHRINE (ADRENALINE) NOREPINEPHRINE DOPAMINE SEROTONIN -AMINOBUTYRIC ACID (GABA)

HORMONES NEUROTRANSMITTERS

PHYSIOLOGICALLY ACTIVE AMINES

DECARBOXYLATION OF PRECURSOR AMINO

ACID

PLP-DEPENDENT, AA DECARBOXYLASES

TYR DOPAMINE, EPI, NOREPINEPHRINE GLUTAMATE GABA HISTIDINE HISTAMINE TRP SEROTONIN

DECARBOXYLATION REACTION
PLP FORMS A SCHIFF BASE WITH AA

RESULTS IN FORMATION OF C CARBANION

UNSTABLE CHARGE BUILDUP ON C WHEN CO2 SPLITS OFF PLP IS AN ELECTRON SINK

IN-CLASS EXERCISE: USING THE STRUCTURE OF

THE AMINO-ACID-PLP SCHIFF BASE AS SHOWN IN CLASS, SHOW (USING ARROWS TO SHOW FLOW OF ELECTRONS) HOW THE C CARBANION FORMED AFTER CO2 SPLITS OFF IS STABILIZED.

GABA
GLUTAMATE GABA + CO2

GLU DECARBOXYLASE

GABA IS THE MAJOR INHIBITORY NEURO-

TRANSMITTER IN BRAIN

GLU IS THE MAJOR EXCITATORY NEUROTRANSMITTER PERMEABILITY TO CHLORIDE IONS

STIMULATION OF NEURONS BY GABA

BENZODIAZEPINES (VALIUM) ENHANCE MEMBRANE PERMEABILITY OF Cl IONS BY GABA GABAPENTIN PROTECTS AGAINST GLU EXCITOTOXICITY

HISTAMINE
HISTIDINE HISTAMINE + CO2

HIS DECARBOXYLASE ALLERGIC RESPONSE

H
1

HISTAMINES INVOLVED IN

RECEPTORS IN GUT, BRONCHI

STIMULATION SMOOTH MUSCLE CONTRN H1 RECEPTOR ANTAGONISTS

CLARITIN, ZYRTEC, ETC

HISTAMINE
HISTAMINES INVOLVED IN CONTROL OF ACID SECRETION IN STOMACH H RECEPTORS 2 STIMULATION HCl SECRETION H ANTAGONISTS 2 CIMETIDINE RANITIDINE H2 RECEPTORS IN HEART

STIMULATION HEART RATE

SEROTONIN
TRP 5-HYDROXYTRYPTOPHAN

TRP HYDROXYLASE REQUIRES 5,6,7,8 TETRAHYDROBIOPTERIN AROMATIC ACID DECARBOXYLASE SMOOTH MUSCLE CONTRACTION BRAIN NEUROTRANSMITTER MELATONIN SYNTHESIZED IN PINEAL GLAND

5-HT SEROTONIN + CO2

SEROTONIN CAUSES

CATECHOLAMINES
EPI, NOREPINEPHRINE, DOPAMINE AMINE DERIVATIVES OF CATECHOL REACTIONS:

TYR L- DOPA

TYR HYDROXYLASE AROMATIC ACID DECARBOXYLASE DOPAMINE -HYDROXYLASE REQUIRES SAM

L-DOPA DOPAMINE + CO2

DOPAMINE NOREPINEPHRINE

NOREPINEPHRINE EPINEPHRINE

L-DOPA AND DOPAMINE

IN SUBSTANTIA NIGRA, CATECHOLAMINE

PRODUCTION STOPS AT DOPAMINE

PARKINSONS DISEASE: DEGENERATION OF SUBSTANTIA NIGRA DOPAMINE TREAT BY GIVING PRECURSOR, L-DOPA DOPAMINE CANNOT CROSS BLOOD/BRAIN BARRIER TRANSPLANTATION OF ADR. MEDULLA CELLS TO BRAIN

L-DOPA A PRECURSOR OF MELANIN

PRODUCTION

IN-CLASS EXERCISE
IN KWASHIORKOR, A DIETARY PROTEIN

DEFICIENCY DISEASE IN CHILDREN, DEPIGMENTATION OF HAIR AND SKIN IS SEEN. EXPLAIN THE BIOCHEMICAL BASIS FOR THIS.

S-ADENOSYLMETHIONINE

ACTIONS OF NOREPINEPHRINE
NOT NEARLY AS ACTIVE AS EPINEPHRINE DURING EXTREME STRESS CIRCULATORY SYSTEM

CONSTRICTS GREAT VEINS (2) VASOCONSTRICTIVE TO SKIN (1) VASOCONSTRICTION (1) EFFECTS ON GI TRACT SPLEEN PANCREAS KIDNEYS

NEUROTRANSMITTER IN THE BRAIN

ACTIONS OF EPINEPHRINE
AS AN INSULIN ANTAGONIST

ACTIVATES MUSCLE GLYCOGEN PHOSPHORYLASE

GLUCOSE-6-P USED IN GLYCOLYSIS

TRIGGERS PHOSPHORYLATION (ACTIVATION) OF HORMONE-SENSITIVE LIPASE IN FAT CELLS

MOBILIZES FAT BY HYDROLYZING TGs

GLYCOGEN BREAKDOWN IN LIVER ACTIVATES GLUCONEOGENESIS IN LIVER INHIBITS FATTY ACID SYNTHESIS

ACTIONS OF EPINEPHRINE
ON CARDIAC MUSCLE -ADRENERGIC RECEPTOR STIMULATION 1 HEART RATE AND CARDIAC OUTPUT

-BLOCKERS BLOOD PRESSURE

DILATES CORONARY ARTERIES (2)

ON SMOOTH MUSCLE (2-ADRENERGIC) IN BRONCHIOLES, FOR EXAMPLE MUSCLE RELAXATION ACTIVATION OF G-PROTEINS

cAMP , ETC

ASTHMA MEDICATIONS

AMINO ACID METABOLISM

SUMMARY 1
SYNTHESIS ESSENTIAL ASPARTATE FAMILY PYRUVATE FAMILY AROMATIC HISTIDINE NON-ESSENTIAL PYRUVATE OXALOACETATE -KETOGLUTARATE 3-PHOSPHOGLYCERATE

AMINO ACID METABOLISM

SUMMARY 2
DEGRADATION TO: PYRUVATE ACETYL-CoA ACETOACETATE -KETOGLUTARATE SUCCINYL-CoA FUMARATE OXALOACETATE

AMINO ACID METABOLISM

SUMMARY 3
KETOGENIC LEU LYS GLUCOGENIC

ALL NON-ESSENTIALS + HIS, VAL,MET

BOTH ILE PHE THR TRP TYR

IN-CLASS STUDY QUESTION

EXPLAIN WHY IT IS POSSIBLE FOR THE

CARBON SKELETON OF EACH AMINO ACID TO BE BROKEN DOWN TO ACETYL-CoA.

AMINO ACID DEGRADATION INTERMEDIATES

Glucogenic Ketogenic

* Both Glucogenic and Ketogenic Purely Ketogenic

Ala Cys Gly

Ser Thr* Trp*

Ile* Leu Lys Thr*

CO2

Pyruvate Acetyl-CoA Acetoacetate

Leu Lys Phe* Trp* Tyr*

Glucose Asn Asp

Oxaloacetate

Citrate

Asp Phe* Tyr* Ile* Met Val

Fumarate

Citric Acid Cycle

Isocitrate
CO2

Succinyl-CoA
CO2

-ketoglutarate

Arg Glu Gln

His Pro