1.

Discuss and trace protein digestion and metabolism

a. Generally:
Proteins Peptides Amino Acids

•Proteases •Endopeptidases •Amino/Carboxypeptidases

b. Protein turnover: protein degraded must be replaced/reused (approximately 75%)

c. Pathways
i. ATP-Independent
1. Proteins degraded in the lysosome by an ATP-independent process:
a. Autophagy
b. Phagocytosis
c. Receptor-mediated endocytosis
ii. ATP & Ubiquitin-Dependent
1. Occurs in the cytosol; requires ATP & Ubiquitin (targets many intracellular CHON for degradation)
for degradation of proteins
2. Ubiquitin
a. Has residues at the amino terminus which determines whether a CHON is ubiquitinated:
i. Met/Ser = retardation of ubiquitination
ii. Asp/Arg = acceleration of ubiquitination
3. CHON:
a. Undergo polyubiquitination (attachment of 4+ ubiquitin molecules at lysine residues)
4. PROTEASOME
a. Recognizes ubiquitin-tagged proteins for degradation, forming short peptides
2. Review Physical and Chemical structures of Aromatic Amino Acids and the Classification of Proteins
a. Aromatic Amino Acids

b. Classification of Proteins
i. Proteins are classified according to their properties (solubility, shape, and presence of non-
protein groups)
ii. Classification according to:
COMPOSITION 3D SHAPE BIOLOGIC FUNCTION DERIVED
Simple Globular Enzymes, Hormones, Primary Proteins
- Made up only of - Soluble and diffuses Storage Proteins, - Proteins undergoing
Amino Acids readily Transport Proteins, slight intramolecular
- Albumin, globulin, - Albumin, globuline, Structural Proteins, arrangement
prolamines, glutein, histones, Protective Proteins, - Proteans,
histones, protamines protamines, insulin, Contractile Proteins, metaproteins,
hemoglobins, IG Toxic Proteins coagulated proteins
Conjugated Fibrous Secondary Protein
- Yields amino acids - Insoluble and tought Derivatives
and other - Collagen, elastine, - Proteoses, Peptones,
components keratin, myosin, Peptides
- Nucleoproteins, fibrinogen
mucoproteins,
glycoproteins,
lipoproteins,
chromoproteins,
metalloproteins,
phosphoproteins
3. Review and discuss the catabolism of the carbon skeletons of amino acids
a. Aromatic Amino Acids
i. Histidine

ii. Tyrosine
1. Converted to amphibolic intermediates, ultimately forming Acetyl-CoA and Acetate
2. Disorders of Tyrosine Metabolism:
a. Tyrosinosis/Type I Tyrosinemia
i. Defect: Fumarylacetoacetate Hydrolase
ii. Untreated = death d/t liver failure
iii. TX: Low Tyr & Phe Diet
b. Richner-Hanhart Syndrome/Type II Tyrosinemia
i. Defect: Tyrosine Aminotransferase
c. Neonatal Tyrosinemia
i. Defect: low activity of p-hydroxyphenylpyruvate
d. Alkaptonuria
i. Defect: Homogentisate Oxidase
ii. Increased Homogentisate
iii. Dark urine after exposure to air (Homogentisate is oxidized)
iv. Later manifestations:
1. Arthritis and Ochronosis
a. d/t homogentisate oxidation to benzoquinone
acetate
iii. Phenylalanine
1. Phenylalanine hydroxylase irreversibly converts Phenylalanine to Tyrosine, and
subsequent reactions follow those of tyrosine
2. Alternative pathway for Phenylalanine exists in patients with Phenylketonuria, of
which its catabolites are mainly excreted.:

iv. Tryptophan
1. Degraded into its amphibolic intermediates via Kynurenine-Anthranilate Pathway
 2. Diagnostic agent for B6 Def
3. Hartnup Disease
a. Impaired intestinal and renal transport of Tryptophan and other Neutral
AAs

4. Review the metabolic pathways of these amino acids and know the importance of its metabolites
a. Histidine
i. Converted to Histamine
1. Functions in allergic reactions, gastric secretion, and circadian rhythm

b. Tyrosine & Phenylalanine (Phe converted to Tyr by Phe Hydroxylase)

i. Tyrosine is converted to cathecolamines (dopamine, norepinephrine, epinephrine)
1. Regulates heart rate, blood pressure, breathin rate, muscle strength, and mental
alertness
c. Tryptophan
i. Serotonin
1. Hydroxylation of Tryptophan to 5-hydroxytryptophan
2. Vasoconstrictor and Stimulator of Smooth Muscle Contraction
ii. Melatonin
1. Regulates sleep-wake cycle
5. Discuss the clinical manifestations of the specific aromatic amino acid defect and its laboratory findings and
know its pathophysiology. Pathophysiology: Please refer to pathways above and the Enzyme defects of each
Aromatic AA
LAB FINDINGS
PHENYLALANINE Classic Phenylketonuria (Severe
Hyperalaninemia):
- Low plasma levels of Phenylalanine
(>20mg/dL)
- Excess is converted to phenylketones,
which is excreted in the urine
(phenylketonuria)
Mild Hyperphenylalaninemia
- 2 – 10mg/dL of plasma Phe
- Above normal plasma Phe but <20mg/dL
- No phenylketones excreted in the urine
Tetrahydrobiopterin Deficiency with
Hyperphenylalaninemia
- Urine and dried blood spots to measure
biopterin and neopterin
- Tetrahydrobiopterin Loading
o Infant is loaded with BH4. Phe levels
drop with BH4 loading
Tetrahydrobiopterin Deficiency without
Hyperphenylalaninemia
- Reduced BH4 and neopterin levels
- Normal Phe
- Reduced dopamine and Homovanillic Acid
TYROSINE Tyrosinemia Type I
- Tyrosinosis/Hereditary
Tyrosinemia/Hepatorenal Tyrosinemia
- Elevated levels of tyrosine,
fumarylacetoacetate and
succinylacetoacetate in urine and/or blood
CLINICAL MANIFESTATIONS
Classic PKU and Mild
Hyperphenylalaninemia
- Child is normal at birth; intellectual
disability develops gradually if
untreated
- Cognitive delay after a few months
- Autism, Purposeless hand
movements, rhythmic rocking, and
athetosis in older untreated children
- Infants have lighter complexion
- Unpleasant odor of Phenylacetic Acid
- Neurologic Signs
o Seizures, spasticity, hyperreflexia,
tremors, microcephaly, enamel
hypoplasia, growth retardation
Tetrahydrobiopterin Deficiency with
Hyperphenylalaninemia
- Hyperphenylalaninemia with
decreases in Serotonin and Dopamine
(BH4 is a cofactor for both tyrosine
and tryptophan hydroxylase)
- Neurologic
o Dystonic Limb Movements, Axial
and Truncal Hypotonia,
Hypokinisea
o Feeding difficulties
o Autonomic abnormalities
o Seizures, hypersalivation,
swallowing difficulties
Tetrahydrobiopterin Deficiency with
Hyperphenylalaninemia
- Lower Limb Dystonia and Tremor
- Torticollis, arm dystonia
- Symptoms improve with sleep
- Parkinsonism may or may not develop
with age
- Adulthood
o Action Dystonia, rigid hypertonia
with tremor
o Serotonin deficiency (sleep
disturbance, cognitive impairment,
impulsivity)
Tyrosinemia Type I
- Symptoms appear 2-6mos.
- Hepatic Crisis
o Fever, irritability, vomiting,
hemorrhage, hepatomegaly,
- Increased levels of a-fetoprotein in
untreated cases
Tyrosinemia Type II
- Richner-Hanhart
Syndrome/Oculocutaneous Tyrosinemia
- Assay of liver tyrosine aminotransferase
activity and tyrosine concentration
Tyrosinemia Type III
- 4-hydroxyphenylpyruvate Deficiency (4-
HPPD)
- Increased levels of Tyrosine (350-
700umol/L)
- Presence of 4-hydroxyphenylpyruvic acid
and its metabolites, 4-hydroxyphenyllactic
acid and 4-hydroxyphenylacetic acid in
urine
Alkaptonuria
- Increased levels of homogentisic acid in
urine and tissue deposits due to defects in
homogentisic acid oxidase; tyrosine levels
are normal
Tyrosine Hydroxylase Deficiency
- Increased levels of tyrosine; decreased
levels of Cathecolamines (dopamine and
norephinephrine)
- Reduced levels of Homovanillic Acid
(dopamine metabolite)
- Serum prolactin is elevated
jaundice, elevated serum
transferase, hypoglycemia
o Boiled cabbage odor due to
increased Methionine metabolites
o May progress to liver failure and
death
o Cirrhosis and Hepatocellular
Carcinoma occur with increasing
age
- Neurologic
o Acute Peripheral Neuropathy
resembling acute porphyria
§ Triggered by a minor infection
§ Severe leg pain, extensor
hypertonia of neck and trunk,
vomiting, paralytic ileus, self-
induced injuries of the
tongue/buccal mucosa
§ Marked weakness and paralysis
which leads to respiratory
failure
- Renal
o Manifested as Fanconi-like
syndrome
o Hyperphosphaturia,
hypophosphatemia, normal anion
gap metabolic acidosis, vitamin d-
resistant rickets
o Nephromegaly, nephrocalcinosis
o GFR failure
o Hypertrophic cardiomyopathy,
hyperinsulinism
Tyrosinemia Type II
- Ocular
o Occurs as early as 6mos
o Excessive tearing, redness, pain,
and photophobia
o Bilateral corneal lesions due to
tyrosine depositions
o Herpetic Corneal Ulcers
- Integumentary
o Develops later in life
o Painful, nonpruritic hyperkeratotic
plaques on the soles, palms, and
fingertips
- Neurologic
o Intellectual Disability
Tyrosinemia Type III
- Developmental delay, seizures,
intermittent ataxia, self-destructive
behavior
Alkaptonuria
- Adulthood
 o Ochronosis
o Alkaptonuric Arthritis
o Mitral and Aortic Valvulitis
o Heart Valve Calcification
o MI
- Childhood
o Darkened urine on standing
Tyrosine Hydroxylase Deficiency
- Mild Form (Dopa-responsive
dystonia)
o Unilateral limb dystonia
- Severe Form (Infantile Parkinsonism,
Infantile encephalopathy)
o Microcephaly
o Developmental delay
o Involuntary limb movements
o Dystonia
o Ptosis
o Autonomic dysfunction
TRYPTOPHAN Hartnup Disease Hartnup Disease
- Aminoaciduria (main; presence of neutral - Cutaneous Photosensitivity
amino acids in urine) o Skin becomes red and rough after
Blue Diaper Syndrome/Drummond Syndrome moderate exposure to sunlight
- Presence of indican (from unabsorbed o Pellagra-like rash after greater
Tryptophan in GIT) exposure to sunlight
- Unsteady, intermittent ataxia
- Irritability, emotional instability,
depression, suicidal tendencies
- Short stature, atrophic glossitis
Blue Diaper Syndrome
- Bluish urine discoloration due to
hydrolysis and oxidation of Indican in
Urine
- Vomiting
- Constipation
- Poor appetite
- Hypercalcemia
- Nephrocalcinosis
- Fever, irritability
- Ocular abnormalities
HISTIDINE Histidinuria
- Increased blood and urinaryHistidine
Urocanic Aciduria
- Increased excretion of Urocanate
Folic Acid Deficiency
- Increased excretion of Figlu
6. Mechanism of the signs and symptoms of the specific amino acid defect. Refer Above

7. Recommended treatment of such amino acid defect

Phenylalanine Classic PKU and Mild Hyperphenylalaninemia
- Phe-Restricted Diet for persistent >6mg/dL blood Phe
- GOAL: Reduce Phe levels in Plasma and Brain
- Phe-Restricted should be done immediately after diagnosis
Tetrahydrobiopterin Deficiency WITH Hyperphenylalaninemia
- Oral supplementation of BH4
- Life-long supplementation of Neurotransmitter Precursors (L-Dopa and 5-
hydroxytryptophan)
Tetrahydrobiopterin Deficiency WITHOUT Hyperphenylalaninemia
- L-DopaCarbidopa Supplementation
- BH4 Supplementation
Tyrosine Type I
- Nitisinone (drug of choice)
o Patient should be restricted from tyrosine and/or phenylalanine-rich diet
- Liver Transplant to alleviate hepatocellular carcinoma
Type II
- Diet low in Tyrosine and Phenylalanine
Type III
- Tyrosine and Phenylalanine-restricted diet
Alkaptonuria
- Nitisinone combined with Phenylalanine and Tyrosine-restricted diet
- For Arhtritis:
o Symptomatic Treatment
Tyrosine Hydroxylase Deficiency
- L-dopacarbidopa supplementation
- Anticholinergics, serotonergic agents, monoamine oxidase-B inhibitors
- Bilateral subthalamic nucleus deep brain stimulation
Tryptophan Hartnup Disease
 - Nicotinic Acid or Nicotinamide and High-protein Diet
Histidine Tourrette Syndrome
- No cure yet; symptomatic management is done
o ADHD Medication
o Antidepressants
o Antiseizure Medications
- Behavioral Therapy