CONVERSION OF AMINO ACIDS TO SPECIALIZED PRODUCTS DR. A. TARAB DEPT. OF BIOCHEMISTRY HKMU
In addition to serving as building blocks for proteins, amino acids are precursors of many nitrogen-containing compounds that have important physiologic functions These molecules include porphyrins, neurotransmitters, hormones, purines and pyrimidines
A. CATECHOLAMINES Dopamine, norepinephrine and epinephrine (adrenalin) are biologically active amines that are collectively termed catecholamines Dopamine and norepinephrine function as neurotransmitters in the brain and in the autonomic nervous system Norepinephrine and epinephrine are also synthesized in the adrenal medulla
Functions: Outside the nervous system, norepinephrine and epinephrine act as regulators of carbohydrate and lipid metabolism Norepinephrine and epinephrine are released from storage vesicles in the adrenal medulla in response to fright, exercise, cold and low levels of blood glucose
They increase the degradation of glycogen and TAG, as well as increase blood pressure and the output of the heart. These effects are part of coordinated response to prepare the individual for emergencies, and are often called the fight-or-flight reactions
Synthesis of catecholamines: - are synthesized from tyrosine Tyrosine is first hydroxylated by tyrosine hydroxylase to form 3,4 dihydroxyphenylalanine (dopa) The enzyme is abundant in the CNS, the sympathetic ganglia and the adrenal medulla and is the rate-limiting step of the pathway
Dopa is decarboxylated in a reaction requiring pyridoxal phosphate to form dopamine, which is hydroxylated by the copper containing dopamine-βhydroxylase to yield norepinephrine Epinephrine is formed from norepinephrine by an N-methylation reaction using SAM as the methyl donor
Synthesis of catecholamines
Degradation of catecholamines: - are inactivated by oxidative deamination catalyzed by monoamine oxidase (MAO) and by O-methylation carried out by catechol-o-methyltransferase (COMT) The aldehyde products of the MAO reaction are oxidized to the corresponding acids
The metabolic products of these reactions are excreted in the urine as vanillylmandelic acid, metanephrine and normetanephrine
Metabolism of catecholamines neurotransmitters
B. CREATINE Creatine phosphate (also called phosphocreatine), is a high energy compound that can reversibly donate a phosphate group to ADP to form ATP Creatine phosphate provides a small but rapidly mobilized reserve of high-energy phosphates that can be used to maintain the intracellular level of ATP during the first few minutes of intense muscular contraction *Note: the amount of creatine phosphate in the body is proportional to the muscle mass
1) Synthesis from glycine and the guanidino group of arginine plus a methyl group from SAM Creatine is reversibly phosphorylated to creatine phosphate by creatine kinase, using ATP as a phosphate donor *Note: the presence of creatine kinase in the plasma is indicative of tissue damage, and is used in the diagnosis of myocardial infarction
Synthesis of creatine and creatinine
2) Degradation creatine and creatine phosphate spontaneously cyclize at a slow, but constant rate, to form creatinine, which is excreted in the urine The amount of creatinine excreted is proportional to the total creatine phosphate content of the body, and thus can be used to estimate muscle mass
When muscle mass decreases for any reason (e.g from paralysis or muscular dystrophy), the creatinine content of the urine falls In addition, any rise in blood creatinine is a sensitive indicator of kidney malfunction, because creatinine is normally rapidly removed from the blood and excreted
c. HISTAMINE - is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion and possibly neurotransmission in parts of the brain A powerful vasodilator, histamine is formed by decarboxylation of histidine in a reaction requiring pyridoxal phosphate It is secreted by mast cells as a result of allergic reaction or trauma
D. Serotonin - also called 5-hydroxytryptamine, is synthesized and stored at several sites in the body By far the largest amount of serotonin is found in cells of the intestinal mucosa Smaller amounts occur in platelets and in the CNS Serotonin is synthesized by hydroxylation of tryptophan
The product, 5-hydroxytryptophan, is decarboxylated to serotonin Serotonin has multiple physiologic roles, including pain perception and regulation of sleep, temperature and blood pressure
Pathway for serotonin and melatonin synthesis
The pineal gland is a pea-sized gland located in the brain The pineal gland secretes the hormone melatonin, which is formed from tryptophan Melatonin seems to be released by the human pineal gland as a response to darkness
Therefore, the pineal gland is thought to be involved in establishing daily biorhythms The pineal gland may also play a role in mood disorders and in a variety of aspects of sexual development
The biological clock (sleepwake rhythm)
E. Melanin - is a water-insoluble polymer of various compounds, derived from tyrosine There are two major forms of melanin: i) eumelanin brown to black in colour ii) pheomelanin yellow to red in colour Functions - occurs in a number of tissues, particularly in the eye, hair and skin
In the epidermis, the pigment-forming cells are called melanocytes Melanin is synthesized to protect underlying cells from the harmful effects of sunlight Synthesis of melanin The first step in melanin formation from tyrosine is a hydroxylation to form dopa and dopaquinone catalyzed by the copper-containing enzyme tyrosine hydroxylase (also called tyrosinase)
Subsequent reactions leading to the formation of brown and black pigments are also thought to be catalyzed by tyrosinase or to occur spontaneously
F. Glutathione Glutathione (GSH) is tripeptide composed of glutamate, cysteine and glycine that has numerous functions within cells GSH serves as a reductant, is conjugated to drugs to make them more water soluble, is involved in amino acid transport across cell membranes (the γ-glutamyl cycle) etc
Synthesis of glutathione
Structure of G-S-S-G
The role of GSH as a reductant is extremely important particularly in the highly oxidizing environment of the erythrocyte Endogenously produced hydrogen peroxide is a toxic substance that, if allowed to accumulate results in the oxidation of haemoglobin to methemoglobin and also causes damage to cell membrane
One function of GSH is to remove hydrogen peroxide in the presence of selenium-dependent glutathione peroxidase 2 G-SH + H 2 O 2 G-S-S-G + H 2 O Glutathione reductase utilizes NADPH as a cofactor to reduce G-S-S-G back to two moles of GSH G-S-S-G + NADPH + H + 2 G-SH + NADP +
Hence, the PPP is an extremely important pathway of erythrocytes for the continuing production of the NADPH needed by glutathione reductase