Bca Protein Metab 2

WAYS OF DETOXIFYING
AMMONIA
Classification of amino acids from a
nutritional point of view
❖ Essential or indispensable amino acids

- can not be synthesized by the body so they
must be provided in the diet
Phe Trp His
Val Thr Arg
Ile Leu
Met Lys
❖ Nonessential or dispensable amino acids
- can be synthesized by the body so they need not
be provided in the diet.
Ways of Detoxifying Ammonia
1. Reversal of the glutamate dehydrogenase rxn
Glutamic acid  -Ketoglutarate + NH3
2. Glutamine formation
Glutamine
Glutamic acid + NH3  Glutamine
synthetase
3. Asparagine formation
Aspartic acid + NH3  Asparagine
4. Urea formation
Transamination
▪ Enzyme: Transaminase or aminotransferase
▪ General reaction:
▪ Enzyme: Aspartate aminotransferase or Glutamate-

oxaloacetate transaminase
▪ Co-enzyme: Pyridoxal Phosphate (Vitamin B6)
Intermediate amino group
Carrier between the amino acid and the keto acid
Catabolic Disposition (Fates) of
Carbon Chains of Amino Acids
Oxidative Deamination
▪ Overall Reaction
Amino Acid Keto acid + NH3
▪ Enzymes involved:
1. Glutamate dehydrogenase
COOH H2O
COOH COOH
(CH2)2 + NAD+ (CH2)2 (CH2)2
CH-COOH NH=C-COOH O=C-COOH
NH2
-Iminoglutaric -Ketoglutarate +
acid NH4 + NADH2
Glutamate
Urea Cycle
Two Forms of CPS
▪ CPS I :
- uses ammonia as its nitrogen donor;
- used in the urea cycle;
- mitochondrial in location;
- absolutely dependent on N-AGA for activity
▪ CPS II :
- uses glutamine as its nitrogen donor;
- involved in pyrimidine synthesis;
- cytosolic in location;
- not affected by N-AGA
Urea Cycle
▪ Enzymes:
1. Carbamoyl PO4
synthetase
2. Ornithine
transcarbamoylase
3. Argininosuccinate
synthetase
4. Argininosuccinase
5. Arginase
“Kreb’s bicycle”
Urea Cycle
UREA CYCLE MUTATED GENE
DISORDER/DEFFICIENCY
NAGS NAGS
CPS CPS I
OTC OTC
CITRULLINEMIA TYPE 1 ASS I
CITRULLINEMIA TYPE 2 SLC2513
ARGINOSUCCINIC ACIDURIA ASL
ARGINASE ARG I
HHH SYNDROME ORNT I

INBORN ERRORS OF UREA SYNTHESIS
1. Hyperammonemia Type I
[Carbamoyl phosphate synthetase]
2. Hyperammonemia Type II
[Ornithine transcarbamylase]
3. Citrullinemia
[Argininosuccinate synthetase]
4. Argininosuccinate aciduria
[Argininosuccinase]
5. Arginemia
[Arginase]
Therapy for urea cycle enzyme deficiencies
has a 3-fold basis
1. To limit protein intake & potential build-up of NH3

- limit ingestion of amino acids
- give levulose to promote excretion of NH3 in feces
- give antibiotics to kill NH3-producing bacteria
2. To remove excess ammonia
- give cpds that bind covalently to amino acids and
produce N-ctg molecules that are excreted in the
urine [Ex. Benzoate + Glycine = Hippuric acid;
Phenylacetate + Glutamine = Phenylacetylgln
3. Replace any intermediates missing from the urea
cycle
Treatment of Ammonia Intoxication
(due to causes other than inborn errors)
▪ Aims of Treatment
- elimination or treatment of precipitating factors
- lowering of blood NH3 levels by decreasing
absorption of proteins
▪ Modes of Therapy
- low protein diet
- Lactulose
- Antibiotics
Metabolic Pathway of Phe/Tyr
▪ Enzymes:
1. Phenylalanine
monooxygenase or
phenylalanine oxidase
or phenylalanine
hydroxylase
2. Homogentisate 1,2-
dioxygenase
3. Tyrosinase
Phenylketonuria (PKU)
Phe hydroxylase
Phe + O2 Tyr + H2O
THB DHB
NADP+ NADPH + H+
THB – Tetrahydrobiopterin; electron donor

DHB – Dihydrobiopterin
NADPH – ultimate electron donor
DHB reductase – enzyme that converts DHB to THB
Types of Phenylketonuria
• Classic PKU – caused by deficiency of
Phenylalanine Hydroxylase
• Hyperphenylalaninemia Type II, III–
deficiency of Dihydrobiopterin reductase
• Hyperphenylalaninemia Type IV, V –
deficiency of Dihydrobiopterin
biosynthesis
Tyrosinemias
1. Type 1 or Hepatorenal tyrosinemia

- deficiency of fumarylacetoacetate hydrolase
- accumulation of fumarylaceto-acetate and
maleylacetate, both of which are alkylating
agents, can lead to DNA alkylation and
tumorigenesis.
- more serious type; leads to liver failure, renal
tubular dysfunction, rickets and polyneuropathy.
Metabolic Pathway of Phe/Tyr
▪ Enzymes:
1. Phenylalanine
monooxygenase or
phenylalanine oxidase
or phenylalanine
hydroxylase
2. Homogentisate 1,2-
dioxygenase
3. Tyrosinase
Metabolic Pathways of Tryptophan
1. Degradation via kynurenine-anthranilate pathway
Tryptophan
tryptophan oxygenase or Trp pyrrolase
N-formylkynurenine
Kynurenine
Vit B2
alternative pathway
Hydroxykynurenine Xanthurenate
kynureninase; Vit. B6 (elevated in B6 def. )
ALA * main pathway
Hydroxyanthranilate Niacin
Acetoacetyl CoA
Inborn Errors of Trp Metabolism
1. Hartnup disease
- defect in the intestinal and renal transport of Trp
- deficiency of Trp pyrrolase
- S/S include pellagra-like skin rash, cerebellar ataxia,
intellectual deterioration.
Tryptophan …
2. Conversion to serotonin
Tryptophan
Hydroxytryptophan
decarboxylase
CO2 * neurotransmitter
Serotonin (5-hydroxytryptamine) * vasoconstrictor
* stimulates smooth
NH3 monoamine oxidase muscle contraction
5-hydroxyindoleacetate * Elevated in carcinoid syndrome

(Argentaffinoma)
Inborn Errors of Trp Metabolism
2. Carcinoid syndrome
- associated with carcinoid tumors occurring in the
small intestines, appendix, colon, stomach.
- S/S are caused by secretion by the tumor of serotonin,
prostaglandins, …
- Serotonin is the most common secretory product of
carcinoid tumors and measurement of urinary 5-HIAA
levels is the most useful diagnostic test.
Tryptophan …
3. Formation of melatonin in the pineal body
Serotonin
acetylase
N-acetylserotonin
methylase; SAM
Melatonin
Inborn Errors of Trp Metabolism [cont’d]
3. Blue Diaper Syndrome

- impaired intestinal and renal absorption of Trp
- familial disorder characterized by hypercalcemia,
nephrocalcinosis, and indicanuria.
Dietary Trp Skatole and Indole

(Large Intestines) absorbed
then goes
to liver
Indican
Excreted in urine
-KG
Transamination
Glu
-Ketoisovaleric acid
CoA, NAD+
dehyrogenase NADH, CO2
Isobutyryl CoA
Acyl CoA DH
Methylacrylyl CoA
Methylmalonic acid semialdehyde
Propionyl CoA
Succinyl CoA
Leucine -KG
Transaminase
Glu
-Ketoisocaproic acid
CoA, NAD+
-Ketoisocaproic
Isovaleryl CoA
Acyl CoA DH
ß-Methylcrotonyl CoA
ß-Hydroxy-ß-methyl
Glutaryl CoA (HMG-CoA)
Acetyl CoA Acetoacetic acid

-KG
Transamination
Glu
-Keto-ß-methylvaleric acid
CoA, NAD+
-Methylbutyryl CoA
Acyl CoA DH
Tiglyl CoA
-Methylacetoacetyl CoA
Propionyl CoA
Methylmalonyl CoA
Succinyl CoA
Metabolic Disorders of Branched-chain AA
1. Maple Syrup Urine disease

- also called branched-chain ketonuria
- absence or deficiency of -keto acid
dehydrogenase
- S/S: odor of urine resembles maple syrup or
burnt sugar; infant is difficult to feed, lethargic and
may vomit; extensive brain damage may occur
Methionine
Inborn Errors
1. Homocystinuria
- Deficiency of
cystathionine
synthetase
2. Cystathioninuria
- Deficiency of
cystathionase
Inborn Errors of Cys Metabolism
1. Cystinuria (Cystine-Lysinuria)
- due to a renal transport defect affecting renal
reabsorptive mechanisms for 4 AA: Cys, Lys, Arg and
ornithine
- S/S:  urinary excretion of Cystine, Lys, Arg, ornithine
- Cystine is insoluble → precipitate in kidney →
Cystine calculi
Biosynthesis of Nutritionally
Nonessential Amino acids
Synthesis of Non-essential
amino acids
1. Glycine Serine
2. Proline Glutamic acid
3. Arginine Glutamic acid
4. Histidine Glutamic acid
5. Tryptophan Alanine
6. Phenylalanine Tyrosine
7. Threonine Glycine
8. Methionine Cysteine
9. Aspartic acid Asparagine
10. Glutamic acid Glutamine
11. Pyruvate Alanine
12. Oxaloacetate Aspartic acid
13. -ketoglutarate Glutamic acid
14. 3-phosphoglycerate Serine
Synthesis of Glutamate
Alpha-ketoglutarate
NH4+
NADPH + H+
glutamate DH
NADP+ H20
Glutamate
Glutamate dehydrogenase reaction (reversal)

Synthesis of Glutamate [cont…]
transaminase
▪ -Ketoglutarate Glutamic acid
amino acid keto acid
▪ Histidine Figlu Glutamic acid
▪ Arginine Ornithine Glutamic acid
▪ Proline Pyrroline-5-carboxylic acid Glutamic a.

amino acids
1. Glycine Serine
Synthesis of Aspartic acid
Transamination
Oxaloacetate Aspartic acid
Glutamic acid -ketoglutarate

amino acids
1. Glycine Serine
Synthesis of Alanine
Pyruvate
Glutamate (or Asp)

aminotransferase
&-ketoglutarate
(or oxaloacetate)
Alanine
Transamination reaction
amino acids
1. Glycine Serine
Synthesis of Glutamine
Glutamate
NH4+
Mg-ATP
glutamine synthetase
Mg-ADP + Pi
Glutamine
Glutamine synthetase reaction

amino acids
1. Glycine Serine
Synthesis of Asparagine
Aspartate
Glutamine
Mg-ATP
asparagine synthetase
Mg-AMP + PPi Glutamic acid
Asparagine
Asparagine synthetase reaction

amino acids
1. Glycine Serine
Synthesis of Serine
3-Phosphoglycerate (from glycolysis)
oxidation
Phosphohydroxypyruvate
transamination
Phospho-L-serine
dephosphorylation
Serine
amino acids
1. Glycine Serine
Synthesis of Glycine & Serine
Serine
FH4
serine
hydroxymethyl
transferase
Methylene FH4
Glycine
amino acids
1. Glycine Serine
Synthesis of Glycine [cont’d…]
2) CO2 + NH3 + N5,N10-methylene FH4
Pyridoxal PO4 Glycine synthase
Glycine + FH4 + NAD
3) Threonine Glycine + Acetaldehyde

cleavage
enzyme
amino acids
1. Glycine Serine
Glyoxylate
Glutamate or Alanine
glycine
aminotransferase
&-KG or pyruvate
Glycine
Choline
Betaine aldehyde
Betaine
Dimethylglycine
Sarcosine
Glycine
amino acids
1. Glycine Serine
Synthesis of Proline
Glutamate
NADH
H20
Glutamate semialdehyde
H20
Pyrrolidine-5-carboxylate
NADH
Proline
Reversal of proline catabolism

amino acids
1. Glycine Serine
Synthesis of Cysteine
Serine + Homocysteine (fr. Methionine)
H20
Cystathionine
H20
Cysteine + Homoserine
amino acids
1. Glycine Serine
Synthesis of Tyrosine
Phenylalanine
Tetrahydrobiopterin NADP
phenylalanine
hydroxylase
Dihydrobiopterin NADPH
O2
H20
Tyrosine
amino acids
1. Glycine Serine
Synthesis of Hydroxyproline and
Hydroxylysine
Proline Lysine
&-ketoglutarate
Pro Lys
hydroxylase hydroxylase
O2, Fe2+
vit. C
O-succinate
Hydroxyproline Hydroxylysine
amino acids
1. Glycine Serine
END

Bca Protein Metab 2

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Bca Protein Metab 2

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WAYS OF DETOXIFYING

❖ Essential or indispensable amino acids

1. Reversal of the glutamate dehydrogenase rxn

Glutamic acid  -Ketoglutarate + NH3

Aspartic acid + NH3  Asparagine

▪ Enzyme: Aspartate aminotransferase or Glutamate-

CITRULLINEMIA TYPE 1 ASS I

CITRULLINEMIA TYPE 2 SLC2513

ARGINOSUCCINIC ACIDURIA ASL

HHH SYNDROME ORNT I

1. To limit protein intake & potential build-up of NH3

THB – Tetrahydrobiopterin; electron donor

1. Type 1 or Hepatorenal tyrosinemia

tryptophan oxygenase or Trp pyrrolase

5-hydroxyindoleacetate * Elevated in carcinoid syndrome

3. Blue Diaper Syndrome

Dietary Trp Skatole and Indole

Methylmalonic acid semialdehyde

Acetyl CoA Acetoacetic acid

1. Maple Syrup Urine disease

Glutamate dehydrogenase reaction (reversal)

amino acid keto acid

▪ Histidine Figlu Glutamic acid

▪ Arginine Ornithine Glutamic acid

▪ Proline Pyrroline-5-carboxylic acid Glutamic a.

Glutamic acid -ketoglutarate

Glutamate (or Asp)

Glutamine synthetase reaction

Mg-AMP + PPi Glutamic acid

Asparagine synthetase reaction

3-Phosphoglycerate (from glycolysis)

2) CO2 + NH3 + N5,N10-methylene FH4

Pyridoxal PO4 Glycine synthase

Glycine + FH4 + NAD

3) Threonine Glycine + Acetaldehyde

Reversal of proline catabolism

Serine + Homocysteine (fr. Methionine)

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