Transcript AMINO ACID BIOSYNTHESIS

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


GLU + NAD(P)+ + H2O  -KG + NH3 +
NAD(P)H + H+
REVERSE RXN  GLU
 GLU

DEHYDROGENASE RXN
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
METHIONINE
PHENYLALANINE
THREONINE
TRYPTOPHAN
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
ASPARAGINE
ASPARTATE
*CYSTEINE
GLUTAMATE
GLUTAMINE
GLYCINE
PROLINE
SERINE
*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
Glutamine
Synthetase
Regulation
(Less Active)
O
O
P
O
CH2
H
O
H
HO
Adenine
O
H
H
OH
Uridylyltransferase
-Ketoglutarate
ATP
Glutamine X
PPi
Adenylyltransferase
PII
Pi X
Adenylyltransferase
UTP
PII
Pi
PPi
O
ATP
O
OH
UMP
P
O
CH2
H2O
O
H
H
HO
Uridylyl-removing Enzyme
Glutamine Synthetase
Uracil
O
H
H
OH
ADP
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


METHYL (-CH3)
FORMALDEHYDE AT N5,N10


AT N5
METHYLENE (-CH2-)
FORMATE



FORMYL (-CH=O)
FORMIMINO (-CH=NH)
METHENYL ( -CH=)
AT N5 OR
N10
AT N5
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-βPHOSPHATE + 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
ASP I
ASP II
ASP III
FEEDBACK INHIB COREPRESSOR
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

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 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)
 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 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
 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


L-DOPA  DOPAMINE + CO2


AROMATIC ACID DECARBOXYLASE
DOPAMINE  NOREPINEPHRINE


TYR HYDROXYLASE
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


TRIGGERS PHOSPHORYLATION (ACTIVATION) OF
HORMONE-SENSITIVE LIPASE IN FAT CELLS




GLUCOSE-6-P USED IN GLYCOLYSIS
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
Ala
Cys
Gly
Ketogenic
* Both Glucogenic and Ketogenic
• Purely Ketogenic
CO2
Glucose
Ile*
Leu•
Lys•
Thr*
Ser
Thr*
Trp*
Pyruvate
Acetyl-CoA
Acetoacetate
Asn
Asp
Citrate
Oxaloacetate
Asp
Phe*
Tyr*
Fumarate
Leu•
Lys•
Phe*
Citric
Acid
Cycle
Trp*
Tyr*
Isocitrate
CO2
Ile*
Met
Val
Succinyl-CoA
-ketoglutarate
CO2
Arg
Glu
Gln
His
Pro