Amino acidsynthesis
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Transcript of Amino acidsynthesis
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