BCHM 451 LIBERTY UNIVERSITY DB2 Outline + Paper ASSIGNMENT 2020.pdf

1. Describe the metabolic fates of phenylalanine; highlighting the synthesis and degradation pathways of

catecholamines (dopamine, norepinephrine and epinephrine), melanin and thyroid hormones.

a. What is phenylalanine? Done

b. How is phenylalanine synthesized/degraded? done

c. How is phenylalanine utilized in catecholamines pathways? (Kuhar; Vegh, 2016) done

d. How is phenylalanine utilized in melanin pathways? (D’mello, 2016) done

e. How is phenylalanine utilized in thyroid hormone pathways? (Rousset,2015) done

2. Describe the biochemical relationships between these disease and phenylalanine metabolism; albinism,

phenylketonuria, Parkinson’s disease and Haloperidol toxicity.

b. MAO/COMT affect in Parkinson’s treatment (Talati, 2009)

c. MAO/COMT affect in Catecholamine synthesis (winter, 1978) https://link-springer-

com.ezproxy.liberty.edu/article/10.1007/BF00426959

d. MAO/COMT affect in OCD (Sampaio, 2015)

4. How can a knowledge of phenylalanine metabolism be useful in the laboratory diagnosis of

a. (Ribeiro, 1991)

b. (Kostyuk, 1991)

Extra phenylalanine in schizophrenic patients.

Phenylalanine, Melanin, Catecholamines, and Thyroid Hormones.

by protein pepsin into smaller peptides that travel through the small intestine until they are hydrolyzed by other

enzymes, transported intracellularly and undergo hydrolysis, and transported in portal blood to liver or

peripheral tissues where they can be taken up and used or continue to pass through circulation until needed. In

the liver, phenylalanine is converted to tyrosine (i.e., L-tyrosine) by phenylalanine hydroxylase (PH); both

phenylalanine and tyrosine are needed for melanogenesis and the synthesis of fumarate and acetoacetate,

thyroxine, catecholamines, and proteins. In turn, products may be beneficial in certain medical conditions

(discussed later).

Moreover, skin color tells an epic tale of human intrepidness and adaptability revealing its variance as a

function of biology. Skin color is all centered on melanin; in fact, light absorption of melanin in skin and hair

increases tyrosinase activity, whereas tyrosine induces melanosome (melanin pigment storage units) synthesis,

and increases tyrosinase activity. Additional enzymes tyrosinase-related protein 1 (TYRP1) and tyrosinase-

related protein 2 (TYRP2) affect the quantity and quality of melanin produced in the body. Little is known

about the degradation of melanin, however, it is suspected that the skin contains enzymes that degrade melanin.5

Furthermore, catecholamines are produced by chromaffin cells in the adrenal medulla. The synthesis of

catecholamines starts with the conversion of phenylalanine to tyrosine by PH which is converted to L-Dopa by

tyrosine hydroxylase (TH). It should be noted that tyrosinase and tyrosine hydroxylase are isozymes, performing

the same function although cellular expressions are different. L-Dopa is processed to dopamine (DA) by L-

and the latter two NT are important for sympathetic innervation. Catecholamines are degraded in the liver by

two enzymes, (COMT) and (MAO)-further discussed in a catechol-O-methyltransferase mono-amine oxidase

subsequent section. By the action of COMT, epinephrine and norepinephrine are converted to metanephrine and

normetanephrine.8

Finally, the thyroid contains two hormones, L-thyroxine (T ) and L-triiodothyronine (T ). Both

hormones are produced in the thyroid gland from tyrosine and iodine. Circulating iodine is trapped in the

thyroid, oxidized by thyroperoxidase (TPO), and bound to tyrosine residues, thyroglobulin (Tg), to form mono-

and di-iodothyronines (MIT and DIT, respectively) and their subsequent spontaneous crosslinking to form T3

and T4.9,10 Deiodinases are essential in controlling local thyroid hormone action during development and

phenylalanine to tyrosine and subsequently after several additional reactions, melanin. There are two forms of

albinism: oculocutaneous albinism (OCA), affecting the skin and eyes, and ocular albinism (OA), affecting

solely the eyes.11 OCA and OA together are subtyped into 10 subgroups, and tyrosinase activity varies within

those groups; however, most subgroups are characterized with low/absent tyrosinase activity and the remaining

subgroups with a normal tyrosine activity. Tyrosine is the rate-limiting step in melanin formation, therefore,

low/absent tyrosinase activity represents a non-pigmented phenotype on the skin or eyes. Additionally, normal

tyrosinase activity, with abnormalities in other enzymes in the pathway, also lead to a non-pigmented

phenotype.11

Moreover, Parkinson’s Disease (PD) is the most common movement disorder and is associated with the

loss of dopaminergic neurons in the basal ganglia causing motor abnormalities, autonomic dysfunction, sleep

In addition, phenylketonuria (PKU) is a genetic amino acid defect resulting from deficiency of hepatic

PH.13,14 The deficiency results in impaired hydroxylation of phenylalanine to tyrosine manifested as elevated

phenylalanine plasma levels and corresponding low tyrosine levels. In PKU, elevated plasma phenylalanine

concentrations may disturb blood-to-brain large neutral amino acid (LNAA) transport and cerebral protein

synthesis.13 Untreated PKU is characterized by mental retardation, primarily in executive function deficits.

Lastly, haloperidol (HAL) is a typical antipsychotic medication and words by decreasing abnormal

excitement in the brain. Acute brain tyrosine depletion attenuates HAL-induced dopamine release and

potentiates haloperidol-induced catalepsy and toxicity. However, effects can be reversed by administration of

COMT and MAO

mostly oxidized by MAO-B. Additionally, COMT is magnesium (Mg ) dependent and has two isoforms that