AMINO ACID BIOSYNTHESIS

NON-ESSENTIAL AMINO ACIDSESSENTIAL AMINO ACIDSSINGLE CARBON TRANSFERS WITH THFPHYSIOLOGIC 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 α-KG + NH3 +

NAD(P)H + H+ REVERSE RXN GLU

GLU SYNTHASE RXN’ GLU NADPH + H+ + GLN + α-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 α-AMINO NITROGEN, IN THE FORM OF GLU, MUST BE CONSIDERED AN ESSENTIAL NUTRIENT

AMINO ACID BIOSYNTHESIS

ESSENTIAL AMINO ACIDS*ARGININE METHIONINE

HISTIDINE PHENYLALANINE

ISOLEUCINE THREONINE

LEUCINE TRYPTOPHAN

LYSINE VALINE

NOTE ARG IS ESSENTIAL IN INFANTS AND CHILDREN MOST SYNTHESIZED ARG ORNITHINE AND

UREA VIA THE UREA CYCLE

AMINO ACID BIOSYNTHESIS

NONESSENTIAL AMINO ACIDS

ALANINE GLUTAMINEASPARAGINE GLYCINEASPARTATE PROLINE*CYSTEINE SERINEGLUTAMATE *TYROSINE

NOTE: CYS GETS ITS SULFUR ATOM FROM MET TYR IS HYDROXYLATED PHE

SO IT’S NOT REALLY NONESSENTIAL

AMINO ACID BIOSYNTHESIS

ALL ARE SYNTHESIZED FROM COMMON METABOLIC INTERMEDIATES

NON-ESSENTIAL TRANSAMINATION OF α-KETOACIDS THAT ARE

AVAILABLE AS COMMON INTERMEDIATES ESSENTIAL

THEIR α-KETOACIDS ARE NOT COMMON INTERMEDIATES (ENZYMES NEEDED TO FORM THEM ARE LACKING)

SO TRANSAMINATION ISN’T 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

↓ ↓ PHE→TYR PYRUVATE ALA TRP ↓ VAL

CITRATE LEU, ILE

↓OXALOACETATE, α-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 α-KETOGLUTARATE 3-PHOSPHOGLYCERATE

SYNTHESIS OF NON-ESSENTIAL AMINO ACIDS

TRANSAMINATION REACTIONS: ONE STEP

PYRUVATE + AA ALANINE + α-KETOACID OXALOACETATE + AA ASPARTATE + α-

KETOACID α-KETOGLUTARATE + AA GLUTAMATE + α-

KETOACID

TRANSAMINASES: EQUILIBRATE AMINO GROUPSREQUIRE PYRIDOXAL PHOSPHATE (PLP)

ALL AAs, EXCEPT LYS, CAN BE TRANSAMINATED MOST TRANSAMINASES GENERATE GLU OR ASP

WHY? LOOK AT MECHANISM OF PLP (PAGE 987 IN TEXT)

A

B

C

SYNTHESIS OF NONESSENTIAL AMINO ACIDS

ATP-DEPENDENT AMIDATION OF ASP, GLU ASN, GLN GLU + ATP + NH3 GLN + ADP + Pi

GLUTAMINE SYNTHETASE NH3 IS TOXIC; IT’S STORED AS GLN

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 α-KG

EXCESS AAs TRANSAMINATED TO GLU OXIDATIVE DEAMINATION OF GLU α-KG

+ NH3 NH3 UREA OR GLN (STORAGE)

↑ α-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 CELL’S 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]

FAR FROM EQUILIBRIUM (IRREVERSIBLE) ENZYME SATURATED NOT ENOUGH ACTIVITY TO ALLOW EQUIL. RATE INSENSITIVE TO [REACT], [PROD] “STEADY STATE” (CONSTANT FLUX) “RATE-DETERMINING STEP”

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 α-KG AND ATP DEACTIVATED BY GLN AND Pi

URIDYL-REMOVING ENZYME INSENSITIVE TO THESE

Pi

ADP

UTP PPi

H2OUMP

ATP

PPi

Uridylyltransferase

Uridylyl-removing Enzyme

X

X

α-Ketoglutarate

ATP

Glutamine

Pi

(Less Active)

(More Active)

Bacterial GlutamineSynthetaseRegulation

BACTERIAL GLUTAMINE SYNTHETASE

IN-CLASS EXERCISE

EXPLAIN THE SIGNIFICANCE OF α-KG AS AN ACTIVATOR OF GLUTAMINE SYNTHETASE

SHOW, IN DETAIL, THE EFFECT OF ↑ LEVEL OF α-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, α-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 + α-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 α-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:

PYRUVATEOXALOACETATEα-KG3-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-6-METHYLPTERIN 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) FORMALDEHYDE AT N5,N10

METHYLENE (-CH2-) FORMATE

FORMYL (-CH=O) AT N5 OR N10

FORMIMINO (-CH=NH) AT N5

METHENYL ( -CH=) AT N5,N10

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

BACTERIA SYNTHESIZE FOLIC ACID SULFONAMIDES COMPETITIVELY INHIBIT

STRUCTURAL ANALOGS OF PABA GOOD ANTIBACTERIAL AGENTS WHY ARE MAMMALS UNAFFECTED?

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 REACTIONSIN-CLASS STUDY QUESTION

DRAW THE STRUCTURES OF THE KETO-ACID PRODUCTS OF THE REACTIONS OF THE FOLLOWING AMINO ACIDS WITH α-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)

PATHWAYS ONLY IN MICRO-ORGANISMS AND PLANTS PROBABLE EVOLUTIONARY LOSS IN MAMMALS PATHWAYS ARE VERY COMPLICATED ACTUAL PATHWAYS VARY ACROSS SPECIES!

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-β-

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 THR THR, ILEASP II NONE METASP III LYS LYS

COREPRESSOR: TRANSCRIPTIONAL REPRESSION

ASPARTATE FAMILY

ALSO CONTROL AT BRANCH POINTS NOTE THE FOLLOWING REACTION:

HOMOCYSTEINE + N5-METHYL-THF MET + THF ENZYME: METHIONINE SYNTHASE (?)

↑ 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-β-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 AMINO-

TRANSFERASES 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 α-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)

SOME INTERESTING CHEMISTRY THIAZOLIUM RING

ACIDIC HYDROGEN “ELECTRON SINK”

TRANSITION STATE STABILIZATION MECH. YLIDS RESONANCE

THE AROMATIC FAMILY

IN PLANTS AND MICRORGANISMS PHE TYR TRP

PECURSORS ARE: PEP ERYTHROSE-4-PHOSPHATE THESE CONDENSE WITH ULTIMATE

CONVERSION TO CHORISMATE

THE AROMATIC FAMILY

CHORISMATE BRANCH POINT FOR TRP SYNTHESIS CHORISMATE ANTHRANILATE TRP CHORISMATE PREPHENATE

PREPHENATE BRANCH POINT FOR PHE, TYR SYNTH

AMINOTRANSFERASES IN EACH FINAL STEP

IN MAMMALS, TYR IS A PRODUCT OF: PHE HYDROXYLATION

THE TRP PATHWAY

TRYPTOPHAN SYNTHASE CATALYZES FINAL 2 STEPS

INDOLE-3-GLYCEROL PHOS INDOLE + GLYC-3-P

INDOLE + SER H2O + TRP

α2β2 BIFUNCTIONAL ENZYME

WHAT ENZYME CLASS?

THE TRP PATHWAY

“CHANNELING” INDOLE IS SEQUESTERED BETWEEN THE

TWO ACTIVE SITES DIFFUSES BETWEEN TWO SITES IT’S NONPOLAR

STUDY QUESTION: WHAT ARE THE BENEFITS OF CHANNELING?

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

PHENYLKETONURIAIN-CLASS STUDY QUESTION

WRITE OUT THE REACTION IN WHICH PHE IS TRANSAMINATED TO PHENYLPYRUVATE, SHOWING STRUCTURES

EXPLAIN WHY CHILDREN WITH A TETRAHYDRO-BIOPTERIN 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-α-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 + α-D-RIBOSE-5-PHOSPHATE PRPP +

AMP α-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 γ-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 Cα CARBANION

UNSTABLE CHARGE BUILDUP ON Cα 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 Cα 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 NEURO-

TRANSMITTER STIMULATION OF NEURONS BY GABA

↑ PERMEABILITY TO CHLORIDE IONS BENZODIAZEPINES (VALIUM) ENHANCE

MEMBRANE PERMEABILITY OF Cl IONS BY GABA GABAPENTIN PROTECTS AGAINST GLU

EXCITOTOXICITY

HISTAMINE

HISTIDINE HISTAMINE + CO2

HIS DECARBOXYLASE

HISTAMINES INVOLVED IN ALLERGIC RESPONSE

H1 RECEPTORS IN GUT, BRONCHI STIMULATION SMOOTH MUSCLE

CONTRN’ H1 RECEPTOR ANTAGONISTS

CLARITIN, ZYRTEC, ETC

HISTAMINE

HISTAMINES INVOLVED IN CONTROL OF ACID SECRETION IN STOMACH

H2 RECEPTORS STIMULATION ↑ HCl SECRETION H2 ANTAGONISTS

CIMETIDINE RANITIDINE

H2 RECEPTORS IN HEART STIMULATION ↑ HEART RATE

SEROTONIN

TRP 5-HYDROXYTRYPTOPHAN TRP HYDROXYLASE REQUIRES 5,6,7,8 TETRAHYDROBIOPTERIN

5-HT SEROTONIN + CO2

AROMATIC ACID DECARBOXYLASE

SEROTONIN CAUSES SMOOTH MUSCLE CONTRACTION BRAIN NEUROTRANSMITTER MELATONIN SYNTHESIZED IN PINEAL GLAND

CATECHOLAMINES

EPI, NOREPINEPHRINE, DOPAMINE

AMINE DERIVATIVES OF CATECHOL

REACTIONS:

TYR L- DOPA TYR HYDROXYLASE

L-DOPA DOPAMINE + CO2

AROMATIC ACID DECARBOXYLASE DOPAMINE NOREPINEPHRINE

DOPAMINE β-HYDROXYLASE NOREPINEPHRINE EPINEPHRINE

REQUIRES SAM

L-DOPA AND DOPAMINE

IN SUBSTANTIA NIGRA, CATECHOLAMINE PRODUCTION STOPS AT DOPAMINE PARKINSON’S 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 (α2) VASOCONSTRICTIVE TO SKIN (α1) VASOCONSTRICTION (α1) 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 β1 -ADRENERGIC RECEPTOR STIMULATION

↑HEART RATE AND CARDIAC OUTPUT β-BLOCKERS ↓ BLOOD PRESSURE

DILATES CORONARY ARTERIES (β2)

ON SMOOTH MUSCLE (β2-ADRENERGIC) IN BRONCHIOLES, FOR EXAMPLE MUSCLE RELAXATION

ACTIVATION OF G-PROTEINS cAMP , ETC

ASTHMA MEDICATIONS

AMINO ACID METABOLISMSUMMARY 1

SYNTHESIS ESSENTIAL

ASPARTATE FAMILY PYRUVATE FAMILY AROMATIC HISTIDINE

NON-ESSENTIAL PYRUVATE OXALOACETATE α-KETOGLUTARATE 3-PHOSPHOGLYCERATE

AMINO ACID METABOLISMSUMMARY 2

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

AMINO ACID METABOLISMSUMMARY 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 INTERMEDIATESAMINO ACID DEGRADATION INTERMEDIATES

CO2

CO2

Pyruvate

Acetyl-CoA Acetoacetate

Citrate

Isocitrate

α-ketoglutarateSuccinyl-CoA

Fumarate

Oxaloacetate

CitricAcidCycle

CO2

Glucose

Ala SerCys Thr*Gly Trp*

Ile*Leu•

Lys•

Thr*

Leu• Trp*Lys• Tyr*Phe*

AsnAsp

AspPhe*Tyr*

Ile*MetVal

Arg HisGlu ProGln

Glucogenic

Ketogenic

* Both Glucogenic and Ketogenic

• Purely Ketogenic