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 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 GLUTAMINE
ASPARAGINE GLYCINE
ASPARTATE PROLINE
*CYSTEINE SERINE
GLUTAMATE *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 -KETOACIDS THAT ARE
AVAILABLE AS COMMON INTERMEDIATES
 ESSENTIAL
 THEIR -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, -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

 TRANSAMINASES: EQUILIBRATE AMINO GROUPS

REQUIRE 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
C

B
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 -KG
 EXCESS AAs TRANSAMINATED TO GLU
 OXIDATIVE DEAMINATION OF GLU  -KG
+ NH3
 NH3  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 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 -KG AND ATP
 DEACTIVATED BY GLN AND Pi

 URIDYL-REMOVING ENZYME INSENSITIVE

TO THESE
Bacterial (Less Active)
Glutamine O

Synthetase O P O CH2
Adenine
O
Regulation O
H
H H
H
HO OH

Uridylyltransferase
-Ketoglutarate
ATP
Glutamine X Adenylyltransferase
PPi Pi X PII
Adenylyltransferase
UTP PPi Pi
PII

O
ATP
O P O CH2
Uracil ADP
OH UMP H2O O
H H
O
H H
HO OH

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
 HOMOCYSTEINEIS 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-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 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)
 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, ILE

ASP II NONE MET
ASP 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

 FIRSTPYR 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)
 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

 2β2 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
PHENYLKETONURIA
IN-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--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 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 (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
 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 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
Ile*
Ketogenic Ala Ser Leu•
Cys Thr* Lys•
* Both Glucogenic and Ketogenic
• Purely Ketogenic Gly Trp* Thr*

CO2
Pyruvate
Glucose
Acetyl-CoA Acetoacetate
Asn Leu• Trp*
Asp Lys• Tyr*
Citrate Phe*
Oxaloacetate
Asp Citric
Phe* Acid Isocitrate
Tyr* Fumarate Cycle
CO2

-ketoglutarate Arg His

Ile* Succinyl-CoA
Met Glu Pro
Val CO2 Gln