This document discusses amino acid biosynthesis. It begins by explaining how diazotrophs fix atmospheric nitrogen into ammonia. It then describes the glutamate dehydrogenase and glutamine synthetase reactions, which are important in amino acid synthesis. The document notes that preformed alpha-amino nitrogen in the form of glutamate must be considered an essential nutrient. It lists the essential and nonessential amino acids, and explains how nonessential amino acids are synthesized from common metabolic intermediates like pyruvate, oxaloacetate, and alpha-ketoglutarate using transamination reactions. The role of tetrahydrofolate in transferring single carbon units for metabolic precursors is also summarized.

1. AMINO ACID
BIOSYNTHESIS
NON-ESSENTIAL AMINO ACIDS
ESSENTIAL AMINO ACIDS
SINGLE CARBON TRANSFERS WITH THF
PHYSIOLOGIC AMINES

2. 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+

3. 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

4. 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

5. 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

6. 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

7. 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

8. SYNTHESIS OF NON-ESSENTIAL
AMINO ACIDS
 ALL (EXCEPT TYR) SYNTHESIZED
FROM COMMON INTERMEDIATES
SYNTHESIZED IN CELL
 PYRUVATE
 OXALOACETATE
 α-KETOGLUTARATE
 3-PHOSPHOGLYCERATE

9. 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 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)

10. A
B
C

12. 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

13. 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

14. 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

15. 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”

16. BACTERIAL GLUTAMINE
SYNTHETASE
 BRIEF REVIEW: REGULATING ENZYME
ACTIVITY
CONTROL OF ENZYME ACTIVITY
 ALLOSTERIC REGULATION
 COVALENT MODIFICATION
 GENETIC CONTROL
 AT LEVEL OF TRANSCRIPTION

17. 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

18. 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

19. Pi
ADP
UTP PPi
H2OUMP
ATP
PPi
Uridylyltransferase
Uridylyl-removing Enzyme
X
X
α-Ketoglutarate
ATP
Glutamine
Pi
(Less Active)
Bacterial
Glutamine
Synthetase
Regulation

20. 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

21. 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)

22. 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)

24. 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

25. NONESSENTIAL AMINO ACID
SYNTHESIS
 SUMMARY POINT:
 ALL NONESSENTIALS (EXCEPT TYR)
ARE DERIVED FROM ONE OF THE
FOLLOWING COMMON INTERMEDIATES:
PYRUVATE
OXALOACETATE
α-KG
3-PHOSPHOGLYCERATE

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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?

32. 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.

33. TRANSAMINATION REACTIONS
IN-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’

34. 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

35. 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

36. ESSENTIAL AMINO ACID SYNTHESIS
 FOUR “FAMILIES”
 ASPARTATE
 LYS
 MET
 THR
 PYRUVATE
 LEU, ILE, VAL (THE “BRANCHED CHAIN”
AMINO ACIDS)
 AROMATIC
 PHE
 TYR
 TRP
 HISTIDINE

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. THE AROMATIC FAMILY
 IN PLANTS AND MICRORGANISMS
 PHE
 TYR
 TRP
 PECURSORS ARE:
 PEP
 ERYTHROSE-4-PHOSPHATE
 THESE CONDENSE WITH ULTIMATE
CONVERSION TO CHORISMATE

44. 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

45. 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?

46. 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?

47. 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

48. 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?

49. 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

50. 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!

51. 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

52. PHYSIOLOGICALLY ACTIVE
AMINES
 THESE ARE DERIVED FROM AMINO ACIDS
 THEY INCLUDE
 EPINEPHRINE (ADRENALINE)
 NOREPINEPHRINE
 DOPAMINE
 SEROTONIN
 γ-AMINOBUTYRIC ACID (GABA)
 HORMONES
 NEUROTRANSMITTERS

53. PHYSIOLOGICALLY ACTIVE
AMINES
 DECARBOXYLATION OF PRECURSOR
AMINO ACID
 PLP-DEPENDENT, AA DECARBOXYLASES
 TYR  DOPAMINE, EPI, NOREPINEPHRINE
 GLUTAMATE  GABA
 HISTIDINE  HISTAMINE
 TRP  SEROTONIN

54. 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.

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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

61. 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.

62. S-ADENOSYLMETHIONINE

63. 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

64. 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

65. 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

66. AMINO ACID METABOLISM
SUMMARY 1
 SYNTHESIS
 ESSENTIAL
 ASPARTATE FAMILY
 PYRUVATE FAMILY
 AROMATIC
 HISTIDINE
 NON-ESSENTIAL
 PYRUVATE
 OXALOACETATE
 α-KETOGLUTARATE
 3-PHOSPHOGLYCERATE

67. AMINO ACID METABOLISM
SUMMARY 2
 DEGRADATION TO:
 PYRUVATE
 ACETYL-CoA
 ACETOACETATE
 α-KETOGLUTARATE
 SUCCINYL-CoA
 FUMARATE
 OXALOACETATE

68. AMINO ACID METABOLISM
SUMMARY 3
 KETOGENIC
 LEU
 LYS
 GLUCOGENIC
 ALL NON-ESSENTIALS + HIS, VAL,MET
 BOTH
 ILE
 PHE
 THR
 TRP
 TYR

69. IN-CLASS STUDY QUESTION
 EXPLAIN WHY IT IS POSSIBLE FOR THE
CARBON SKELETON OF EACH AMINO ACID
TO BE BROKEN DOWN TO ACETYL-CoA.

70. AMINO ACID DEGRADATION INTERMEDIATESAMINO ACID DEGRADATION INTERMEDIATES
CO2
CO2
Pyruvate
Acetyl-CoA Acetoacetate
Citrate
Isocitrate
α-ketoglutarate
Succinyl-CoA
Fumarate
Oxaloacetate
Citric
Acid
Cycle
CO2
Glucose
Ala Ser
Cys Thr*
Gly Trp*
Ile*
Leu•
Lys•
Thr*
Leu•
Trp*
Lys•
Tyr*
Phe*
Asn
Asp
Asp
Phe*
Tyr*
Ile*
Met
Val
Arg His
Glu Pro
Gln
Glucogenic
Ketogenic
* Both Glucogenic and Ketogenic
• Purely Ketogenic