BIOCHEM B Causes of Phenylketonuria

Protein Metabolism 2 1. Absence of major enzyme (Phe Hydroxylase)

Dra. Santos 2. Absence of DHB, NADPH or both
3. Absence of enzyme that will reduce DHB to THB
(DHB reductase)
PHENYLALALINE AND TYROSINE
If you cannot convert Phe to Tyr, it will now follow a minor
pathway which is the production of phenylpyruvic,
phenyllactic and phenylacetic acid. These are the 3
ketoacids that will accumulate in PKU. There will be
excretion of these ketoacids in the urine gives a
mousy odor of the urine.
If Phe accumulates, there will be mental retardation;
because even though there is an amino acid, but it is
excessive, it is toxic in the brain.

2 most outstanding manifestations of PKU:

1. Mental retardation
o Due to the accumulation of Phe
2. Mousy odor of the urine
o Due to the excretion of the 3 ketoacids
(Phenylpyruvic, Phenyllactic,
Phenylacetic acid)

Enzymes Treatment
Phenylalanine monooxygenase or Phenylalanine Give the baby a milk preparation without Phe
oxidase because the Phe accumulation is toxic.
Homogentisate 1,2-dioxygenase
Tyrosinase ALKAPTONURIA

Tyrosine (non-essential AA) can be synthesized by Phe.

Inborn Errors:
Phenylketonuria (PKU)
Alkaptonuria
Albinism
Tyrosinemia

PHENYLKETONURIA (PKU)
Most common disease caused by a deficiency of
an enzyme of amino acid metabolism
Inability to convert Phe to Tyr
Triad of Alkaptonuria
The complete reaction involved in the conversion of Phe
Ochronosis (connective tissue pigmentation)
and Tyr is:
Arthristis
Black urine (homogenistic acid in the urine)

ALBINISM
No enzyme that will convert DOPA to melanin
(Tyrosinase deficiency) no pigmentation
whitish color
THB Tetrahydrobiopterin; electron donor
TYROSINEMIA
DHB Dihydrobiopterin
NADPH ultimate electron donor
Tyrosinemia Type I
DHB REDUCTASE enzyme that converts DHB to THB
AKA Hepatorenal Tyrosinemia
Fumaylacetoacetate hydrolase deficiency
Reaction: Oxygenation
Cannot convert Fumarylacetoacetate to
Major Enzyme: Phe hydroxylase
Acetoacetate
2 co enzymes: DHP and NADPH
Accumulation of maleyacetoacetate and
fumarylacetoacetate

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 More fatal because it causes liver failure, kidney
failure and can lead to tumorigenesis because B2 & B6 DEFICENCY
the 2 substances that accumulate are DNA
alkylating agents and that can cause tumor
formation.
(-) CONVERSION OF TRP
Tyrosinemia Type II TO NIACIN
AKA Oculocutaneous Tyrosinemia/ Richner-
Hanhart Syndrome
Tyrosine aminotransferase deficiency
NIACIN DEFICIENCY
Less serious type
Oculo = eyes; Cutaneous = skin
Manifested by eye and skin lesions

Derivatives of Phe And Tyr PELLAGRA

Thyroid Hormone
Melanin
Norepinephrine
DERMATITIS
Epinephrine
DIARRHEA
DEMENTIA
TRYPTOPHAN

Derivatives of Trp B6 Deficiency OH-Kyrurenine is channelled towards

1. Niacin (Vitamin B3) - Major derivative Xanthyrenic acid formation Xanthurenic acid in urine
2. Serotonin Basis for Tryptophan Load Test
3. Melatonin
Tryptophan Load Test
KYNURENINE-ANTHRANILATE PATHWAY test for Vitamin B6 deficiency
give the patient Trp then measure amount of
Xanthurenic acid in the urine
Xanthurenic acid B6 deficiency

Ala (non-essenial AA) can be synthesized from Trp

(essential AA).

SEROTONIN
Neurotransmitter in the brain that causes smooth
muscle contraction of arterioles and bronchioles
Vasoconstrictor

MELATONIN
Also a derivative of Trp
Sleep-inducing; regulation of circadian rhythm

Inborn Errors:
Hartnup Disease
Blue Diaper Syndrome
Carcinoid Syndrome

Pathway that converts Trp to Niacin HARTNUP DISEASE

In the conversion of Trp to Niacin, you need 2 Trp oxygenase/pyrrolase deficiency
vitamins: B2, B6 Manifestations of pellagra

CARCINOID SYNDROME
Accumulation of Serotonin
5-HIAA (5-OH-indoleacetic acid) in the urine
(excretory form of serotonin)

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BLUE DIAPER SYNDROME
There is impaired intestinal and renal absorption
of Trp it will go to the large intestines
converted to indole and skatole indole is
absorbed goes to the liver converted to
indican indican excretion in the urine blue
urine
IMPAIRED INTESTINAL AND RENAL
ABSORPTION OF TRP
TRP WILL GO TO THE LARGE INTESTINES
HISTIDINEMIA
Histidase deficiency
(-) conversion of Histidine to Urocanic acid
(ketoacid derived from histidine; normally a
component of the sweat glands)
Dx: Skin Biopsy
o Absence of urocanic acid in sweat
Histidine can also be converted to Glu by passing
through formation of FIGLU (Formiminoglutamic acid). To
convert FIGLU to Glu, you need THFA [Tetrahydrofolic
acid (Vitamin B9)]

(-) Folic acid (-) conversion of FIGLU to Glu excreted

TRP CONVERTED TO INDOLE AND SKATOLE in the urine
Basis for FIGLU excretion test

FIGLU Excretion Test

INDOLE IS ABSORBED
test for Folic Acid deficiency
AKA Histidine Load test
Give the patient His measure amount of FIGLU
INDOLE GOES TO THE LIVER in urine
FIGLU excretion (+)folic acid deficiency

INDOLE CONVERTED TO INDICAN Derivatives of Histidine

Histamine
Carnosine, Anserine
o Used for copper metabolism
INDICAN EXCRETION IN THE URINE

BRANCHED-CHAIN AMINO ACIDS CATABOLISM

BLUE URINE All amino acids are catabolised in the liver
except the branched-chain AAs.
VALINE, LEUCINE, ISOLEUCINE
Manifested also by Hypercalcemia and
They are metabolized in the BRAIN and MUSCLES.
nephrocalcinosis
These 3 amino acids follow the same steps
o elevation of Ca in the blood kidney
stone formation

HISTIDINE

Inborn Errors:
1. Histidinemia
2. Urocanic Aciduria

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Steps METHIONINE
1. TRANSAMINATION Proceeds to the formation of CYSTEINE
o Enzyme keto acid
Val a-ketoisovaleric acid
Leu a-ketoisocaproic acid
Ile a-keto-B-methylvaleric acid

2. DECARBOXYLATION
o Removal of CO2 CoA form
Val a-ketoisovaleric acid DH
Leu a-ketoisocaproic acid DH
Ile a-keto-B-methylvaleric acid DH

*Collectively, these 3 dehydrogenases can be

called as alpha-ketoacid decarboxylase.

Inborn Errors:
Maple syrup urine disease
Isovaleric academia
S-Adenosyl-Methionine (SAM)
MAPLE SYRUP URINE DISEASE Derived from Met
Inborn error associated with the branched-chain Active methyl donor
amino acids Donor of methyl group in the following reactions:
Alpha-ketoacid decarboxylase deficiency o Creatine synthesis
Accumulation of the 3 keto acids excreted in o Choline synthesis
the urine maple syrup odor of the urine o Epinephrine systhesis
o Similar to PKU (3AA are responsible for its
mousy odor) In the conversion of Met to Cysteine, you pass through
(+) Mental retardation the formation of HOMOCYSTEINE.
o Accumulation of Val, Leu, and Ile is toxic very dangerous substance when it accumulates
to the brain in the body
Tx: Prevent intake of the baby of Val, Leu, and Ile
HOMOCYSTEINE ACCUMULATION
ISOVALERIC ACIDEMIA
Inborn error associated with Leucine
Isovaleryl CoA DH deficiency
Accumulation of isovaleryl CoA CORROVE TO LININGS OF BLOOD
Manifestation: Cheesy odor of breath and fluids VESSEL WALLS

HMG CoA
Important substance derived from Leu
CHOLESTEROL EASILY ATTACHES
An obligatory intermediate in cholesterol TO ARTERIAL WALLS
synthesis and ketogenesis

LYSINE
ATHEROSCLEROSIS
Inborn error:
Hyperlysinemia

HYPERLYSINEMIA HEART
STROKE BLINDNESS
KIDNEY
ATTACK FAILURE
Saccharopine dehydrogenase deficiency (Coronary
(Cerebral (Retinal
(Renal
Accumulation of Lys Arteries)
Arteries Arteries)
Arteries)
Inhibits the enzyme ARGINASE of the urea cycle
urea cycle stops hyperammonemia
ammonia intoxication
If the adrenal medulla is normal, hypertension at a young
THREONINE age can be associated with increased Homocysteine.
Proceeds to the formation of GLYCINE Then drugs to lower both BP and Homocysteine should be
given.

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How to lower down Homocysteine levels? o Source of C4 C5 N7 of purine ring
Homocysteine can be converted to Cysteine in 3. Component of Glutathione
the presence of Vitamin B6. o Gly + Cys + Glu
o But it does NOT work if you always give 4. Conjucates with cholic acid to form Glycocholic
B6 because usually in Homocysteine acid (bile salt)
accumulation, there is an o Bile satls for lipid absorption
accompanying deficiency of the 5. Conjugates with Benzoic acid Hippuric acid
enzyme Cystathionine synthetase. o One way to detoxify benzoic acid in the
Convert it back to Methionine body
o Done by giving a high dose of Folic acid 6. Creatine synthesis
(Vitamin B9) and Vitamin B12 o Gly + Arg + Met
o VITAMIN B12
toxic to the liver if it accumulates
only B complex stored in the liver
BIOSYNTHESIS OF NON-ESSENTIAL
can cause hepatic damage

only given if Homocysteine is
AMINO ACIDS
elevated and NOT as a
preventive measure
Normal req. of B12/day: 5 MICROGRAMS ENZYME AMINO ACID
Homocysteine Tx (B12/day): 500MICROGRAMS Glu DH Glu
Gln Synthetase Gln
Inborn Errors: Aminotransferase/ Other amino acids
Homocystinuria Transaminases
Cystathioninuria
GLUTAMIC ACID
HOMOCYSTINURIA a-ketoglutarate
No manifestations except elevation of BP. o by adding an amino group
Cystathionine synthetase deficiency o Through transamination where a-
ketoglutarate is the acceptor of amino
CYSTATHIONINURIA group
Cystathionase deficiency Histidine (through FIGLU)
Arginine
Proline (intercovertible)
CYSTEINE
Proceeds to the formation of Pyruvate GLUTAMINE
Glu + NH3 (through Glutamine synthetase)
Inborn Errors: o Major rxn on how brain detoxifies NH3
Cystinuria
Cystinosis PROLINE
Glutamic acid (interconvertible)
CYSTINURIA and CYSTINOSIS
Both are manifested by: Cystine stone formation ALANINE
in kidneys Pyruvate (by adding an amino group)
Tryptophan
GLYCINE
Simplest amino acid ASPARTIC ACID
Major route: Glycine Synthase reaction Oxaloacetate (by adding an amino group)
o Major enzyme that will catabolise Gly
Can be converted to Serine and vice versa ASPARAGINE
(interconversion) Aspartic acid (by adding an amino group and
Ketoacid from Gly: GLYOXYLIC ACID transamination)

TYROSINE
NOTE! Interconversion is only possible if they are BOTH Phenylalanine (through Oxygenation)
NON-ESSENTIAL amino acids.
SERINE
3-phosphoglycerate (MAJOR SOURCE)
Uses of Glycine: o Intermediate of glycolysis
1. Heme synthesis Glycine (interconvertible)
o Gly + Succinyl CoA o Needs FH4 (active form of Folic acid);
2. Purine synthesis o Needs Serine hydroxymethyltransferase

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GLYCINE Carrier of long chain fatty acids
Glycine Synthase Pathway Lysine + SAM
o CO2 + NH3 + FH4 For weight reduction but only effective if
Serine (interconvertible) with exercise
o Needs FH4 (active form of Folic acid) CYS Coenzyme A
Threonine (through cleavage) Taurine
Glyoxylic acid (by adding an amino group) Cystine
Choline HIS Histamine (allergic reactions)
Ergothioneine, Carnosine, Anserine
CYSTEINE ARG Nitric Oxide (NTA; vasodilator, smooth muscle
Methionine relaxant)
Creatine
SUMMARY OF SYNTHESIS OF NON-ESSENTIAL AA Putrescine, Spermidine & Spermine
TYR Thyroid Hormine
REVERSIBLE Melanin
Glycine Serine NE and Epi
Proline Glutamic acid GLU GABA
Aspartic acid Asparagine Natural tranquilizer
Glutamic acid Glutamine If not synthesized convulsive seizures
Pyruvate Alanine Glu GABA through decarboxyulation
Oxaloacetate Aspartic acid Coenzyme: PLP (Pyridoxal PO4 or Vit B6)
Alpha-ketoglutarate Glutamic acid TRP Serotonin
Indole & Skatole
IRREVERSIBLE Melatonin
Arginine Glutamic acid Niacin
Histidine Glutamic acid
Tryptophan Alanine CREATINE SYNTHESIS
Phenylalanine Tyrosine
Threonine Glycine
Methionine Cysteine
3-phosphoglycerate Serine

SPECIALIZED PRODUCTS DERIVED FROM AMINO ACID

AA DERIVATIVES
GLY Bile salts
1. Glyocoholic acid
2. Glycohenodeoxycholic acid

Hippuric acid
Heme (Gly + Succinyl CoA)
Creatine (Gly + Arg + Met)
Purine (C4 C5 N7)
REACTION 1:
ALA Carnasine and Anserine
Between Arg and Gly
for the enhancement of copper uptake &
TRANSAMINIDATION
activation of myosin ATPase)
o Transfer of R-group
2 Impt AA in Carnsine & Anserine
Arg is basic has an amino group on R position.
1. Beta-alanine
Transfer of R group of Arg to Gly
-amino group attached on beta carbon
Gly Guanidoacetate (Glycocyamine)
2. Histidine
REACTION 2:
Co-enzyme A
Transmethylation
SER Phosphorylation reactions o Transfer methyl group from SAM
THR Forming Creatine
TYR
MET Polyamines (Spermidine & Spermine) REACTION 3:
Have hypothermic and hypotensive Dehydration
properties o Removal of water
Epinephrine o Converting creatine to creatinine
Needs SAM to convert NE Epi Phosphorylation
Creatine PO4 o Converting creatine to Creatine PO4
Choline (Ethanolamine + SAM) (high energy compound)
Carnitine
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GLUCOSE-ALANINE CYCLE

A cycle that means you can convert alanine to

glucose
o Gluconeogenesis breaks down your
muscle proteins then you get Ala;
o Ala goes to the liver and converted to
Pyruvate
o Then gluconeogenesis converts Pyruvate
to Glucose blood sugar level
Used to maintain blood sugar when a person is
not eating

NITROGEN BALANCE
Refers to the difference between total nitrogen
intake and total nitrogen loss in feces, urine, and
perspiration.

Nitrogen IN = Nitrogen OUT

Protein IN = Protein OUT
Anabolism = Catabolism

(+) NITROGEN BALANCE

Intake > Output
Anabolism/Synthesis > Catabolism
Observed in:
o Growth
o Pregnancy
o Convalescence

(-) NITROGEN BALANCE

Intake < Output
Anabolism < Catabolism
Synthesis < Breakdown
Observed in:
o Following surgery
o Prolonged illness
o Metabolic stress
o Advanced cancer
o Lack of an essential AA
o Inadequate dietary CHON
o Starvation and malnutrition
Effect: very rapid weight loss

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