IV: Mitochondrial Function (cont’d).
HEPATIC DETOXIFICATION OF
a) monoamines, alcohol, toluene
b) dietary or endogenous purines
(meat), heme (red meat) & bilirubin,
1
a) Detoxification of monoamines catalysed by
mitochondrial outer membrane MAO
e.g.,
dopamine
norepinephrine
tyramine
phenethylamine
octylamine
serotonin
outer
membrane
MONOAMINE OXIDASE
R-CHNH2
Flavin-containing amine oxidase
R-CH=NH (imine)
O2
H2O2
NAD+
NADH
R-CHO
aldehyde
dehydrogenase
inner
membrane
NH3
ATP,
HCO3urea
cycle
UREA
R-COOH
b-oxidation
CO2
2
Amine specificity for the two isoforms (A & B) in humans
MAO A preferentially metabolizes serotonin.
MAO B preferentially metabolizes phenethylamine, dopamine.
MAO inhibitor + dietary amines or proprietary drugs
MAOB inhibitor deprenyl (selegiline) similar to phenethylamine and increases brain
dopamine levels. This is used to treat Parkinson’s disease.
But “Hypertensive crisis” is a hyperadrenergic state induced by MAO inhibitors +
pressor amines (e.g., tyramine in cheese,beer,wine or soya sauce) or proprietary drugs
(e.g., L-DOPA, mazindol, ephedrine, etc).
Cheese
Cheese
Tyramine (mg/g)
Tyramine (mg/g)
Cheddar cheese, old
1530
English Stilton
1157
Beer
2-11
Blue
998
Sherry Wine
3
Mozzarella
158
Chianti Wine
25
Feta
76
Processed cheese slice
nil
Perry, 1996. http://www.vh.org/adult/provider/psychiatry/CPS/19.html
3
b) Detoxification of alcohols by matrix ALDH2
Covalently binds
to protein-NH2
(ADH)
ETHANOL
cytosolic alcohol
dehydrogenase
NADH
Methyl
pyrazole
acetaldehyde
ANTABUSE
(disulfiram)
or cyanamide
NAD+
NAD+
aldehyde
dehydrogenase
(ALDH)
NADH
acetate
ADH
Chromosome # 4
Caucasians
99% normal
ALDH
9, 12, 17
90% normal
Japanese
40% deficient
90% atypicial
ATP
CoASH
CO2
TCA
cycle
acetylCoA
Suscept. to alcoholism
Appearance social drinking
10% (>)
< 10%
-flushing
4
c) Benzoic acidosis induced by toluene glue sniffing
Toluene
Benzaldehyde
Benzyl alcohol
ADH
Cyt P-450
CH3
CH2OH
ER
CHO
CYTOSOL
ALDH1/
ALDH2
MITOCHONDRIA
COOH
URINE
CONHCH2COOH
Benzoic acid
ATP
CoA
Hippuric acid
Benzoyl-CoA
synthetase
Benzoyl-CoA
glycine
Teratogen Update: Toluene teratology. 55, 145-51, (1997)
5
8. Hemoprotein toxicity diseases
caused by heme or bilirubin
A) Rhabdomyolysis (drug induced)
releases myoglobin and heme and causes
kidney mitochondrial damage
B) Kernicterus:- bilirubin causes neonatal
brain mitochondrial damage
6
A) Myoglobin mediated rhabdomyolysis rarely caused by statins
STATIN Drug BAYCOL withdrawn by BAYER, 2001
Muscle Cell
Drug reactive metabolites
Mitochondrial/cytotoxicity
Myoglobin release
Massive muscle breakdown
CRUSH INJURY
Or if LAIN IMMOBILE for
hrs (e.g. EtOH, heat stroke)
a) x10 creatine
phosphokinase
b) Dark brown granular
casts in urine
Acid
Mb Fe accumulates in kidney renal tubule
Acid
lipid peroxidation (proximal tubule)
mitochondrial toxicity
KIDNEY Failure
(7% of all cases of acute renal failure)
Spontaneous myalgias
Muscle tenderness,
Weakness, malaise, fever
DEATH
THERAPY
1.) NaHCO3 base
2.) Desferoxamine
CMAJ 165(5) pg 632 (2001); J. Biol. Chem. 273, 31731-7 (1998)
7
B) Hemoglobin/heme mediated brain damage
ie. Kernicterus (brain damage caused by bilirubin in the
newborn (hyperbilirubinemia))
• re-emergence (due to shorter hospital time, breastfeeding)
• danger signs onset of jaundice 3 days following birth, vomiting, lethargy, poor
feeding, fever, high pitched crying.
• plasma bilirubin > 340 uM = exchange transfusion therapy
plasma bilirubin > 240 uM = Phototherapy (blue light)
Drug therapy Sn protoporphyrin (inhibits heme oxygenase).
Hemoglobin
Heme oxygenase of reticuloendothelial cells
of spleen, liver, kidney
• Bilirubin
Glucuronyl
Transferase
Appears at 7d
after birth
binds to
serum albumin
released
by competing
fatty acids or
drugs
bilirubin
brain mitochondrial
toxicity (hearing
loss? brain damage
encephalopathy)
Glucuronide
conjugated
bilirubin.
• 0.3% mortality (yellow staining of brain)
• family history, hemolytic diseases, Gilbert’s disease, diabetes (erythrocyte fragility),
8
G6PD deficiency (Pediatrics 106, 1478-80 (2000), sickle cell.
Metabolic pathway of heme degradation to bilirubin and
detoxification of bilirubin by glucuronidation.
(M=methyl,V=vinyl and P=propionate represent heme side chains
Fe2+
CO
Heme
Oxygenase
NADPH:
P450
Reductase
NADPH
O2
NADP+
NADPH
NADP+
H2O
NADPH
NADPH
Biliverdin
Reductase
NADP+
UDP
UDP-glucuronic acid
UDP-glucuronosyl transferase
JAUNDICE
Antioxidant, but at high concn.
TOXIC TO NEONATAL
BRAIN MITOCHONDRIA
9
9. HEME BIOSYNTHESIS BY
MITOCHONDRIA AND GENETIC
DISEASES
A) Heme biosynthesis for cytochromes, etc.
B) Genetic diseases: Porphyrias and porphyrin toxicity
C) Oxidative degradation of heme to bilirubin
10
A) HEME BIOSYNTHESIS
and porphyria diseases
11
Cytochrome Heme Synthesis - Overall picture
12
Heme synthesis
• Heme required for synthesis of mitochondrial
cytochromes and endoplasmic reticular P450s.
• Heme required for bone marrow synthesis of
hemoglobin and muscle myoglobin
• STEP 1 for heme synthesis is the synthesis of
aminolevulinic acid (ALA) from succinyl CoA of
the citric acid cycle and glycine
13
Heme biosynthesis in bone marrow (hemoglobin)
and liver (cytochromes)
ALA SYNTHESIS AND TOXICITY
Mitochondrial Matrix
H+
NH
COO
2
COO
+
CH2
CH2
C
R.L.S.
ALA synthetase
CH2
CoA
pyridoxal
CH2
C
Glycine
Succinyl CoA
succinate
1
Feedback inhibition
by heme
(also induces heme
oxygenase)
O
citric
acid
cycle
COO
CH2
COO
S
CO2 + CoA
O
 Aminolevulinate
(ALA)
CO2 + CoA
-ketoglutarate
dehydrogenase
complex
Fe, O2
NH4+, O 2
ROS
DNA strand breaks
-ketoglutarate
Therefore ANAPLEROTIC
reaction required to replace
succinyl CoA in citric acid
cycle.
C NH3
H2
COO
CH2
DNA ADDUCTS
LIVER CANCER
CH2
C
C
H
ALA synthetase induced by:
1) Heme deficiency due to excess P450
synthesis/induction e.g., by barbiturates
Sulfonamides: Therefore an increase in
urine porphyrins
2) ERYTHROPOIETIN
(formed by kidneys) improves quality
of life of patients on kidney dialysis.
3) Acute intermittent porphyria or ALA
dehydratase deficiency. or lead
4) LEAD
HEME BIOSYNTHESIS
STEP II
(CYTOSOL)
ALA accumulates
a) Acute intermittent porphyria
b) Lead
ALA toxicity
1) Brain
Neuropsychiatric problems in
acute porphyria,
2) Liver necrosis / cancer
particularly if Fe overload
Therapy
1) HEME arginate
2) High carbohydrate
glucose-6-P
O
H2O2
NADPH
GSH reductase
GSH peroxidase
O
Arch Biochem Biophys. 373, 368-74, (2000)
4,5-dioxovaleric acid (DOVA)
14
Erythropoietin synthesised by kidney induces hemoglobin synthesis
in bone marrow (replaces blood transfusion!)
15
Heme Biosynthesis - STEP 2 in the cytosol (4 enzymes 2-5)
COOH
LIVER/BONE MARROW cyto sol
COOH
COOH
HOOC
Cutaneous Porphyria
Porphyria
Cutanea
Tarda
HN
NH
coproporphyrinogen I
non-e nzymatic
* Acute Porphyria
HN
NH
Hydroxymethyl bilane
5
HOOC
COOH
COOH
COOH
HOOC
CYP1A2
COOH
COOH
HOOC
Uroporphyrinogen I
HN
NH
P
A
Symmetrical
HO
A
P
NH
HN
N
HN
HN
NH
HOOC
COOH
HOOC
3
COOH
4
Acute
phosp hobilinogen
Interm ittent
deamin ase
Porphyria*
NH
HOOC
COOH
P
COOH
HOOC
Congenital
Erythropoietic
Porphyria
A
A
COOH
Uroporp hyrinogen III
s ynthas e
NH
HN
NH
HN
CYP1A2
P
Uroporphyrin
(UROPORPHYRIA)
HOOC
COOH
NH2
HOOC
HOOC
Porphobilinogen
(PBG)
2
Uroporphoryrinogen
decarboxylase
COOH
Porphyria
Cutanea
Tarda
COOH
ALA Dehydratase
Deficiency
PBG
Porphryia *
SYNT HASE
r.l.s
polymorphism
-4CO2
COOH
NH
HN
STEP 3
COOH
NH
STEP 1
1
5
HN
O
H2N
ALA
COOH
COOH
Coproporphyrinogen III
16
Heme Biosynthesis - STEP 3 - mitochondrial final steps (3 enzymes)
COOH
Acu t e Po rp h y ria
* Cu tan eo u s Po rp h y ria
COOH
STEP 2
NH
HN
NH
HN
Hered itary 6
Co p ro p o rp h y ria *
O2
CO2
Cop roporph yrinog en
oxidase
COOH
COOH
Cop roporph yrinog en III
m ito ch o n d ria l
in term em b ra n e
sp a ce
Varieg ate
Po rp h y ria *
Pro t o p o rp h y ria
8
7
N
N
Fe
N
Fe2+
NH
N
N
HN
COOH
HEME
NH
O2
i.m.
r.l.s
COOH
HN
Pro t o p o rp h y rin o g en
o x id ase
Ferro ch elatase
N
NH
HN
i.m.
COOH
COOH
Protoporph yrin IX
COOH
COOH
Protoporph yrinogen IX
MITOCHONDRIA
17
B) PORPHYRIAS
I. Enzymes Inhibitors causing porphyria
II. Genetic porphyrias
18
I. ENZYME INHIBITORS CAUSING PORPHYRIA
PORPHYRIA - Greek “porphyros” (purple urine) an over-production
disease. Often neuropsychiatric (syphilis much more so).
2) ALA dehydratase - lead
5) Uro’gen decarboxylase - PCBs, dioxin, lead, cadmium, hexachlorobenzene
(fungicide - seeds). Mitochondrial oxidase - steroids (birth control pills)
and estrogens
8) Ferrochelatase – lead
II. GENETIC PORPHYRIAS (Emerg Med Clin.N Am 23 (2005)885-899)
2) ALAD deficiency porphyria (Seminars in Liver Disease, 18, 95-101, 1998)
excrete ALA not PBG, symptoms like  (neurological).
19
Scriber et al. (eds).
Metabolic and molecular
basis of inherited disease.
7th ed. 1995, p.2124.
20
3) Acute intermittent porphyria (i.e. phosphobilinogenin deaminase deficiency) excrete
ALA and PBG , the most common hepatic porphyria)- MEDALERT bracelet
1. Symptoms - excrete PBG and ALA in the urine , high plasma PBG/ALA
- severe abdominal pain, nausea, vomiting, hypertension(cardiovascular)
then CNS - anxiety, insomnia, confusion, hallucination, paranoia then
peripheral neuropathy - fatal respiratory paralysis. Liver cancer.
2. a. PBG deaminase deficiency - gene locus 11q24 (>100 mutations), autosomal
dominant 1:10,000-50,000 but 1:1000 in N. Sweden (Lapland)
b. Precipitated by phenytoin, phenobarbital drugs, alcohol, fasting,
hormones estrogen, stress, infection or lead poisoning
3. Biochemistry of neurotoxicity
a. heme deficiency   P450 drug metabolism   tryptophan dioxygenase
brain tryptophan  brain serotonin mitochondrial cytochromes (mitoch.disease)
b.  ALA  “ROS”, mitochondrial DNA damage.
4. Therapy –ALA with heme arginate (taken up by liver not b.m.), high glucose
5. Mouse model (PBG knockout) - called Vincent! - behavioural studies
Suspects - Van Gogh, King George III(?) (Absinthe for insomnia)
6.Diagnosis :- Patients urine exposure to sunlight (reddish brown fluorescence)
21
4) Congenital erythropoietic porphyria (Erythroid,
Photosensitive)
-Fe overload of b.m., uroporphyrin overload of skin and erythrocytes
 hemolysis
1. Symptoms: skin lesions (light) , risk of infection in early infancy
Anemia (hemolysis)
Teeth reddish brown (fluorescence)
2. Uroporphyrinogen III synthase deficiency
• Uroporphyrinogen I and coproporphyrin I accumulation in the skin,
bone marrow, erythrocytes, urine, plasma
3. Treatment: activated charcoal (oral); b.m. transplant; gene therapy for bone
marrow; blood transfusion to stop erythropoiesis in b.m.
4. Only 200 diagnosed so far; werewolf, vampires (early childhood sensitive
to light skin blisters, infection  disfigures) is not porphyria
22
5) Porphyria Cutanea Tarda - “heme deficiency and uroporphyrin
overload of liver” (Photosensitive; commonest porphyria;readily treated).
1. Symptoms: lesions on backs of hands and face due to photosensitization by
uroporphyrin I, III or uroporphyrinogen. Abdominal pain, neural,psychiatric.
ALA,porphobilinogen.
2a. Diagnosis :-  urinary uroporphyrin >> coproporphyrin.
b. Uroporphyrinogen decarboxylase deficiency (liver but also erythrocyte in
type II): or hexachlorobenzene or dioxin induced CYP 1A2.
(Turkey bread disaster).
Also Fe uroporphyrinogen III synthase - uroporphyrin I.
c. Candidate hemochromatosis gene leads to diagnosis of hemochromatosis
3. Precip. by alcohol, hepatitis C virus, estrogen (birth control, post-menopause, prostate, pregnancy), Fe.
4. Biochemistry - inactivation of decarboxylase (-SH enzyme) by “ROS” from
reduced P450/P450 reductase/Fe
5. Therapy:- Fe removal (phlebotomy or desferoxamine and ascorbic acid)
- chloroquine  endocytosis and releases uroporphyrin chloroquine
complex from hepatocytes
- heme?
23
6) Hereditary Coproporphyria - coproporphyrinogen oxidase deficient,
chronic fatigue syndrome. - hepatic porphyria
Symptoms: liver cancer
7) Porphyria variegata - protoporphyrinogen oxidase 50% deficient. –
hepatic and skin porphyria
Gene locus 1q2320. 20,000 S. Africans descended from a Dutch lady in 1688
who went to S. African for marriage to another Dutch settler .
Now 3/1000 S.Africans have this!
Symptoms: skin and acute porphyria if exposed to sunlight,neurovisceral
symptoms (abdominal pain),liver cancer
Diagnosis :- plasma fluoresces when exposed to UV.
Precipitated by sunlight
Treatment: increase ALA synthetase by heme arginate, glucose ( NADPH) ?
24
8) Erythropoietic protoporphyria - associated with liver cancer, red urine
“porphyrin and Fe overload disease” “Skin photosensitive”
a. Ferrochelatase decreased 75-90%
b. Symptoms: photosensitive skin (infancy),velvet knuckles, black liver
c. Biochemistry - protoporphyrin IX accumulates in erythrocyte membranes
and liver; intramitochondrial Fe accumulates in bone marrow - skin photosensitivity results from protoporphyria IX effluxing erythrocytes into
plasma.
d. Treatment – topical sunscreens and oral beta-carotene (ROS scav.?)
e. Diagnosis –incr. protoporphyrin in erythrocytes,plasma,bile,feces
I. Liver transplant; operation is difficult as operating room must be
kept dark (only yellow acetate filters)
II. Abdominal burns; transfused blood is destroyed as blood difficult
to store.
25
C) OXIDATIVE DEGRADATION OF
HEME TO BILIRUBIN
(a brain neurotoxin in babies)
26
Detoxification function of the liver
a) heme toxin oxidation to bilirubin
b) detoxification of bilirubin
by glucuronidation or albumin
albumin
LIVER
CO
phagosome
Heme
oxygenase
27
Degradation of heme
STAGE 1
Hemoglobin of old
erythrocyte trapped
in spleen
HEME
O2 + NADPH
Heme oxygenase (ER)
H2O + NADP+
exhaled
Fe3+
CO
Bone marrow
transferrin
M
O
V
M
C
H
N
H
P
P
C
H
N
M
C
H
N
H
V
M
O
N
H
Excreted by Reptiles
and birds
Biliverdin
H2O soluble
NADPH + H+
Biliverdin Reductase
Modified from
Fig. 28-31 Stryer
4th Ed.
NADP+
M
O
M
V
N
H
C
H
Fat soluble
P
P
N
H
C
H2
M
M
N
H
C
H
V
N
H
O
BILIRUBIN (Neurotoxin to babies)
ANTIOXIDANT
NEONATAL
JAUNDICE
Bilirubin accumulates in
newborns.
(destroy with sunlight).
Plasma Serum Albumin Complex
LIVER
28
STAGE II - ligandin in hepatocyte surface membrane traps bilirubin
from plasma and helps transport it into the liver where it is glucuronidated
Albumin
- bilirubin
(a GSH transferase)
29
COO
COO
COO
M
M
V
M
M
V
O
H
+
O
N
H
C
H
C
H2
N
H
C
H
N
H
OH
UDP
H
Bilirubin
OH
UDP-glucuronate
UDP
Endoplasmic reticulum
UDP-glucuronosyl
transferase (UGT 1A1*)
COO
O
H
H
*mutated gene
in Gaucher’s disease
(carried by 15% of
population)
H
OH
O
OH
H
OH
M
O
H
OH
O
N
H
H
C
COO
M
V
N
H
O
C
H
M
M
N
H
C
H2
N
H
C
H
V
N
H
O
BILIRUBIN MONOGLUCURONIDE
UDP gluc. + UGT 1A1
BILIRUBIN DIGLUCURONIDE
(Soluble bilirubin diglucuronide secreted
into the bile)
30
Mitochondrial Function (Con’t).
10. a) N-Catabolism of Amino Acids
(The Urea Cycle) and the
Detoxification of Ammonia (very toxic)
b) N-Catabolism of Purines
• reperfusion injury and drug therapy
• Genetic diseases: HGPRT
• Gout, Lesch-Nyhan syndrome
31
Disposal of nitrogen by mitochondria a)
Cytosol
The urea cycle: Detoxification of NH3
(note: urea cycle enzyme in blue)
citrulline
+
aspartate
ALANINE
-ketoglutarate
synthetase
arginosuccinate argininos uccinase
aspartate
aminotransferase
Alanine
aminotransferase
oxaloacetate
Pyruvate
malate
malate
dehydrogenase
UREA
ornithine
Pi
phospho-enol-pyruvate
INNER MITOCHONDRIAL MEMBRANE
Pyruvate
oxaloacetate
transporter
transporter
malate
NAD+
glutamate
Alanine
aminotransferase
H2O
arginas e
fumarase
glutamate
H+
arginine
+
fumarate
glutamate
dehydrogenase
-ketoglutarate
NADH
citrulline
ornithine
tr ans carbamoylas e
Alanine
NH3
carbamoyl
phosphate
ornithine
2 ATP
Mitochondrial
Matrix
+ HCO 3 -
CO2
carbamoyl phosphate
synthetase
32
Mitochondrial Function (Con’t).
Formation of urea from amino acids
transaminase
dehydrogenase
Urea cycle
dehydrogenase
Glutamate
-ketoglutarate
33
IV: Peroxisomes Function
• β-oxidation of fatty acids but oxidase forms H2O2
• Glyceraldehyde is metabolised to D-glycerate and glucose via
glycolate (glycolate oxidase forms H2O2 and glyoxylate)
• Catalase detoxifies H2O2 to form oxygen and H2O and cooxidises
other substrates, including phenols, formic acid, formaldehyde, and
methanol.
• Glyoxylate detoxified by peroxisomal alanine:glyoxylate
transaminase to form glycine & pyruvate. Otherwise glyoxylate would
be oxidised by lactate dehydrogenase to oxalic acid which causes
oxalate stone formation & kidney damage.
• Biosynthesis of bile acids and ether phospholipids
34
V: CYTOSOLIC FRACTION
N-catabolism of purines
Glycogen synthesis and glycogenolysis
35
Disposal of nitrogen (Con’t):
b) N-catabolism of purines in the cytosol & peroxisomes
HGPRT + PRPP
HGPRT + PRPP
Voet pg. 714.
36
Cytosolic Fraction
1) N-catabolism of purines can be lethal
Reperfusion Injury
e.g. Myocardial infarction
or Paraplegia
a)
ISCHEMIC STAGE
• Lack of O2no ATP synthesis by heart muscle mitochondria.  ADPAMPhypoxanthine
accumulates and leaves muscle cell to enter endothelial cell.
• Acidosis causes endothelial cell xanthine dehydrogenasexanthine oxidase
• Acidosis results from marked increase in glycolysis to form ATP + lactic acid (to keep cells alive
by maintaining ATP levels)
b) Reperfusion of O2
• O2 is the substrate for xanthine oxidase
Accumulated xanthine
and hypoxanthine
Xanthine
oxidase
O2
(Endothelial cell)
•Damaged endothelial and muscle cells (ischemic toxicity)
release factors which recruit neutrophils (inflammatory reaction activated NADPH oxidaseO2*-.
37
Drugs which prevent reperfusion injury
1) Allopurinol – inhibitor of xanthine oxidase
2) Desferal – Complexes Fe2+
3) Antioxidants e.g. Lazeroids (upjohn) to prevent membrane lipid
peroxidation
4) Removal of H2O2 by NADPH (e.g. glucose) or GSH (e.g. methionine)
or dietary Se.
H2O2
OH
Catalase (activated by NADPH)
H 2O
GSH Peroxidase
GSSG + H2O
2 GSH
5) Anti-inflammatory drugs (e.g. indomethacin or phenylbutazone)
6) Ca2+ Blockers
38
Treatment or to prevent Ischemic damage (reperfusion injury)
OH
OH
C
N
C
C
N
CH
HC
C
N
H
H
N
Y
P
T h e
a d m
C
C
N
X
A
N
A
T
H
C
C
X
N
HC
N
O
OH
L
H
IL
a
n
t
i
n
C
N
O
N
N
h
HO
P
E
U
R
I
N
O
L A
C
e
C
N
L
H
C
L
O
N
x
i
d
a
s
N
O
X
A
N
(
T
o
H
x
I
y
s y n t h e s i s
o f
u r a t e
f r o m
i n i s t r a t i o n
o f
a l l o p u r i n
39
2) Purine catabolism can be painful and cause joint damage
•
•
•
•
Figure 22.22 (Voet) – By James Gilroy
Defects in excretion of uric acid and/or partial deficiency in HGPRT activity due to mutation in HGPRT gene
Uric acid precipitation in joints – crystals activate leukocytes  H2O2 and O2*-  arthritis.
Adults (0.55%) in males
Often suffered by over-achieving males with too much drive and ambition (e.g. pharmacists).
Drugs which trigger gout
• Anticancer drug treatment of acute leukemia resulting in destruction of nucleic acids and accumulation of
uric acid.
• Long term diuretic treatment (impair glomerular filtration)
Risk Factors
• Eating too much meat (purines e.g. xanthine)
• Alcohol ingestion increases hypoxanthine
40
• age, male gender, high body mass index, hypertension.
Cytosolic Fraction
3) Genetic Deficiency of HGPRT
LESCH-NYHAN SYNDROME – X-linked recessive (X-chromosome gene)
50% of cells have a complete deficiency of salvage enzyme HGPRT
(Hypoxanthine – guanine phosphoribosyl transferase) or lyase (ASLI) which catalyses:
synthetase
adenylsuccinate
HGPRT
Hypoxanthine + PRPP
Guanine + PRPP
Lyase(ASLI)
PPi + IMP
PPi + GMP
XMP
adenosine
AMP
Nucleotide
synthesis
Results in enormous overproduction of PRPP,hypoxanthine,uric acid.
PRPP (5-phosphoribosyl-a-pyrophosphate)
ATP
Ribose-5-phosphate
ADP
2
P3 O
O
CH 2
H
Pyrophosphokinase
H
H
O

H
O
OH
OH
O
P
O
O
O
P
O
O
41
Children with LESCH-NYHAN SYNDROME
(Incidence 1:380,000) (HGRPT deficiency)
Children
• Neurological dysfunctions ( serotonin metabolism)
• Aggressive or self mutilating but affectionate, quick to laugh,
likeable and open.
• Tend to chew their lips and finger tips
• Mental retardation
• Cerebral palsy and spasticity
• Obscene gestures
• Flinging their feces
• Die before reaching the age of 10 due to renal failure.
• If mild enough, gout will develop into adulthood.
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DRUG THERAPY
ALLOPURINOL is the most useful drug for treatment of GOUT.
Inhibition of uric acid production because xanthine oxidase (terminal
step to uric acid production) is inactivated by allopurinol.
However, neurological problems associated with LESCH-NYHAN SYNDROME
which have been attributed to PRPP and  de novo purine synthesis can not be
alleviated by allopurinol. Allopurinol will prevent uric acid stones accumulating
in the kidney and will prevent kidney infections and hematuria.
NEUROLOGICAL TOXIC MECHANISM UNKNOWN
HGPRT, which is required for purine synthesis is still functionally deficient and
PRPP accumulates.Dopamine neuron function is still lost and neurological problems
persist.
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The End
• Don’t memorize 9, 21, 31, 33, 35, 37, 43
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