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AMINO ACID BIOSYNTHESIS. NON-ESSENTIAL AMINO ACIDS ESSENTIAL AMINO ACIDS SINGLE CARBON TRANSFERS WITH THF PHYSIOLOGIC AMINES. AMINO ACID BIOSYNTHESIS. “FIXING” OF ATMOSPHERIC N 2 DIAZOTROPHS FIX N 2 TO NH 3 IN MICRO-ORGANISMS, PLANTS, LOWER ANIMALS: GLU DEHYDROGENASE RXN

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amino acid biosynthesis

AMINO ACID BIOSYNTHESIS

NON-ESSENTIAL AMINO ACIDS

ESSENTIAL AMINO ACIDS

SINGLE CARBON TRANSFERS WITH THF

PHYSIOLOGIC AMINES

amino acid biosynthesis2
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 biosynthesis3
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 biosynthesis4
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 biosynthesis5
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 biosynthesis6
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
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
SYNTHESIS OF NON-ESSENTIAL AMINO ACIDS
  • ALL (EXCEPT TYR) SYNTHESIZED FROM COMMON INTERMEDIATES SYNTHESIZED IN CELL
    • PYRUVATE
    • OXALOACETATE
    • -KETOGLUTARATE
    • 3-PHOSPHOGLYCERATE
slide9

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)
slide10

A

C

B

synthesis of nonessential amino acids
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
slide13

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
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
slide15

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”
slide16

BACTERIAL GLUTAMINE SYNTHETASE

  • BRIEF REVIEW: REGULATING ENZYME ACTIVITY

CONTROL OF ENZYME ACTIVITY

      • ALLOSTERIC REGULATION
      • COVALENT MODIFICATION
      • GENETIC CONTROL
        • AT LEVEL OF TRANSCRIPTION
bacterial glutamine synthetase17
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
slide18

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 synthetase20
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
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 synthesis22
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 synthesis24
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
slide25

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
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 c 1 units to metabolic precursors
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
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
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
tetrahydrofolate30
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
tetrahydrofolate31
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?
tetrahydrofolate32
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
TRANSAMINATION REACTIONSIN-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
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
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
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
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
slide38

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
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
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 family41
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 family42
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
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 family44
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
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 pathway46
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?
slide47

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
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
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 biosynthesis50
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 biosynthesis51
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
PHYSIOLOGICALLY ACTIVE AMINES
  • THESE ARE DERIVED FROM AMINO ACIDS
  • THEY INCLUDE
    • EPINEPHRINE (ADRENALINE)
    • NOREPINEPHRINE
    • DOPAMINE
    • SEROTONIN
    • -AMINOBUTYRIC ACID (GABA)
  • HORMONES
  • NEUROTRANSMITTERS
physiologically active amines53
PHYSIOLOGICALLY ACTIVE AMINES
  • DECARBOXYLATION OF PRECURSOR AMINO ACID
    • PLP-DEPENDENT, AA DECARBOXYLASES
  • TYR  DOPAMINE, EPI, NOREPINEPHRINE
  • GLUTAMATE  GABA
  • HISTIDINE  HISTAMINE
  • TRP  SEROTONIN
decarboxylation reaction
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.
slide55
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
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
slide57

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
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
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
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 exercise61
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.

actions of norepinephrine
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
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 epinephrine65
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
AMINO ACID METABOLISMSUMMARY 1
  • SYNTHESIS
    • ESSENTIAL
      • ASPARTATE FAMILY
      • PYRUVATE FAMILY
      • AROMATIC
      • HISTIDINE
    • NON-ESSENTIAL
      • PYRUVATE
      • OXALOACETATE
      • -KETOGLUTARATE
      • 3-PHOSPHOGLYCERATE
slide67

AMINO ACID METABOLISMSUMMARY 2

  • DEGRADATION TO:
    • PYRUVATE
    • ACETYL-CoA
    • ACETOACETATE
    • -KETOGLUTARATE
    • SUCCINYL-CoA
    • FUMARATE
    • OXALOACETATE
amino acid metabolism summary 3
AMINO ACID METABOLISMSUMMARY 3
  • KETOGENIC
    • LEU
    • LYS
  • GLUCOGENIC
    • ALL NON-ESSENTIALS + HIS, VAL,MET
  • BOTH
    • ILE
    • PHE
    • THR
    • TRP
    • TYR
in class study question
IN-CLASS STUDY QUESTION
  • EXPLAIN WHY IT IS POSSIBLE FOR THE CARBON SKELETON OF EACH AMINO ACID TO BE BROKEN DOWN TO ACETYL-CoA.
slide70

Glucogenic

Ile*

Leu•

Lys•

Thr*

Ketogenic

Ala Ser

Cys Thr*

Gly Trp*

*Both Glucogenic and Ketogenic

•Purely Ketogenic

CO2

Pyruvate

Glucose

Acetyl-CoA

Acetoacetate

Asn

Asp

Leu• Trp*

Lys• Tyr*

Phe*

Citrate

Oxaloacetate

Asp

Phe*

Tyr*

Citric

Acid

Cycle

Isocitrate

Fumarate

a-ketoglutarate

Arg His

Glu Pro

Gln

Ile*

Met

Val

Succinyl-CoA

AMINO ACID DEGRADATION INTERMEDIATES

CO2

CO2