Question

1. Describe the metabolic fates of phenylalanine; highlighting the synthesis and degradation pathways of catecholamines (dopamine, norepinephrine and epinephrine), melanin and thyroid hormones.
2. Describe the biochemical relationships between these disease and phenylalanine metabolism; albinism, phyenylketonuria, parkinson's disease and Haloperidol toxicity.
3. Describe the pharmacological importance of the enzymes COMT and MAO.
4. How can a knowledge of phenylalanine metabolism be useful in the laboratory diagnosis of pheochromocytoma?

Describe the role of ethanol in cellular energy supply, the metabolism of ethanol (alcohol), the regulation of its metabolism and the disease conditions associated with its metabolism especially - hypoglycemia, ketoacidosis, hepatic steatosis, Vitamin deficiency, and acetaldehyde toxicity (you should feel free to discuss other diseases that are directly related to ethanol metabolism). (1000 words)

Answer 1

1. The metabolic fates of phenylalanine - the synthesis and degradation pathways of catecholamines (dopamine, norepinephrine and epinephrine), melanin and thyroid hormones.

The metabolic fates of phenylalanine

Phenylalanine is a primary amino acid that is abundant in dietary protein. It's main metabolic pathway yields the amino acid Tyrosine, which is involved in the production of Melanin pigments. Phenylalanine is an essential nutrient, but some individuals are born with a genetic disorder, phenylketonuria (PKU), that prevents them from metabolizing phenylalanine.  If PKU is untreated, phenylalanine accumulates in the body, becomes converted into phenylpyruvate and the individual usually develops seizures, brain damage and mental retardation. PKU is usually treated by a diet to avoid foods high in phenylalanine. Structurally, phenylalanine is closely related to dopamine, epinephrine (adrenaline) and tyrosine. Phenylalanine is converted into tyrosine, which then becomes converted into catecholamine (dopamine, norepinephrine and epinephrine) neurotransmitters.

The synthesis and degradation pathways of catecholamines (dopamine, norepinephrine and epinephrine)

Catecholamines are synthesized from Tyrosine (Tyr). The initial step involves hydroxylation to dihydroxyphenylalanine (DOPA), catalyzed by the enzyme Tyr hydroxylase (TH). Once formed, DOPA is rapidly decarboxylated to Dopamine (DA) by aromatic L-amino acid decarboxylase. Neurons use DA as a transmitter in  no further enzymatic modification occurs. Neurons that use norepinephrine (NE) as a transmitter contain an additional enzyme, DA-b-hydroxylase, that converts DA to NE. Neurons using epinephrine as a transmitter contain phenylethanolamine-N-methyl transferase (an additional enzyme), which is responsible for catalyzing the conversion of NE to epinephrine. The initial step in the pathway, Tyr hydroxylation, is rate limiting and thus controls the rate of synthesis through the entire pathway.

2. The biochemical relationships between albinism, phyenylketonuria, parkinson's disease and Haloperidol toxicity with phenylalanine metabolism.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism caused by a deficiency or inactivity of the enzyme phenylalanine hydroxylase. This enzyme is responsible for conversion of the phenylalanine (Phe) to tyrosine (Tyr). If left untreated, high levels of Phe cause intellectual disability, microcephalia, behavioral disturbances, dermopathy and epilepsy.

Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, affecting millions of elderly people. The motor symptoms of PD, such as rigidity, tremor or bradykinesia, are caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta. The signs of parkinsonism might be caused by the depletion of DA activity in the brain. Major causes of neurodegeneration are mitochondrial impairment and oxidative stress. In addition to this, the catecholamine (CA) metabolism is a unique feature of catecholaminergic neurons and represents an additional source for reactive oxygen species (ROS) production.

Haloperidol toxicity is due to severe extrapyramidal reactions such as tremor, rigidity and an intense feeling of physical restlessness, referred to as akathisia. The effects of long-term administration of the dopamine D(2) receptor antagonist haloperidol on Parkinsonian symptoms have been shown to persist after cessation of the drug treatment. Haloperidol reduces the efficacy of levodopa in parkinson's disease by blockade of dopamine receptors in the corpus striatum. Another possibility is the mechanism by which haloperidol causes parkinsonism.

Albinism is related to PKU, the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a “musty odor” to the baby's sweat and urine. Phenylalanine is metabolized into acetoacetic acid and fumaric acid via tyrosine. Tyrosinase deficiency can cause albinism with a lack of the neurotransmitter dopamine, resulting in symptoms of schizophrenia.

3. Two major enzymes are responsible for catecholamine catabolism in the brain are catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A). COMT is an Mg2+ dependent enzyme involved in the inactivation of certain catecholamines (norepinephrine, epinephrine, and dopamine) and also plays an important role in neuropsychiatric disorders. MAO-A are enzymes that catalyze the metabolism of monamines including norepinephrine, dopamine and serotonin.  

4. Tyrosine serves as a precursor for the production of catecholamines. Catecholamines can further produce metanephrine and normetanephrine in the presence of an enzyme Catechol-O-methyl transferase (COMT). Hence, the knowledge of phenylalanine metabolism can be useful in the diagnosis of pheochromocytoma. The diagnosis of pheochromocytoma are the establishment of urinary normetanephrine and platelet norepinephrine.

Ethanol promotes oxidative stress, both by increasing ROS formation and by decreasing cellular defense mechanisms. These effects of ethanol are prominent in the liver, the major site of ethanol metabolism in the body.

The pathway of ethanol metabolism. Ethanol is metabolized into acetaldehyde by the enzyme alcohol dehydrogenase (ADH) and the microsomal enzyme cytochrome P450 2E1 (CYP2E1). The ADH enzyme reaction is the main ethanol metabolic pathway involving an intermediate carrier of electrons, namely, nicotinamide adenine dinucleotide (NAD+). Acetaldehyde is rapidly metabolized by aldehyde dehydrogenase (ALDH) in the mitochondria to acetate and NADH and acetate is eventually metabolized in the muscle to carbon dioxide and water.

Acetate from ethanol metabolism is  associaated with various disease conditions.

Hypoglycemia is a condition in which your blood sugar (glucose) level is lower than normal. Glucose is our body's main energy source. Hypoglycemia is often related to diabetes treatment.

Ketoacidosis is a serious complication of type 1 diabetes and much less commonly of type 2 diabetes. Ketoacidosis happens when our blood sugar is very high and acidic substances called ketones build up to dangerous levels in our body.

Hepatic steatosis is an accumulation of fat in the liver. It is an accumulation of fat in the hepatic cells and can cause complications in cases of obesity, alcohol intoxication and hepatic disorders.

Vitamin deficiency is the condition of a long-term lack of a vitamin. It is caused by not enough vitamin intake (primary deficiency), or due to an underlying disorder such as malabsorption (secondary deficiency).

Acetaldehyde Toxicity. Acetaldehyde is toxic when applied externally for prolonged periods, an irritant and a probable carcinogen. Acetaldehyde naturally breaks down in the human body but has been shown to excrete in urine of rats.