Synthesis and significance of biological substances: Serotonin, Melatonin, Catecholamines.

 

1. Synthesis and Significance of 5-HT:

• Also called “Serotonin”.

• There are three main types of cells that store serotonin (5-hydroxytryptamine) -

• Blood platelets

• Neurons in the brain and the intestinal myenteric plexus,

• Mucosa of the gastrointestinal tract contains enterochromaffin cells.

• The enterochromaffin cells and serotonergic neurons produce serotonin from L-tryptophan, 

• Platelets uptake the serotonin from blood.

• In the cytosol of brain cells, the enzyme L-tryptophan hydroxylase (TPH) is involved in the synthesis of serotonin through the conversion of L-tryptophan to 5-hydroxytryptophan. 

• Serotonin synthesis in neurons is regulated by this enzyme in a similar fashion to that by the related enzyme L-tyrosine hydroxylase, which converts L-tyrosine to L-dihydroxyphenylalanine (L-DOPA). 

• Functions of Serotonin:

• Mood elevator.

• Involved in bone metabolism.

• Involved in cardiovascular health.

• Involved in eye health.

• Involved in blood clotting.

• Involved in neurological disorders.

2. Melatonin:

• Secreted by “Pineal Gland” and regulates sleep.

• Secretion depends on light, secreted in dim light i.e. during night, effects are minimum during day.

• Synthesized in the body from a similar pathway of Serotonin.

• Functions:

• Sleep quality and mood are improved. 

• Melatonin functions can delay aging processes. 

• Scavenging free radicals,

• Stabilizing biological rhythms, 

• Stimulates the immune system. 

• Decreases susceptibility to stress.

3. Catecholamines:

• The substances containing catechol nuclei in their chemical structure are called “Catecholamines”.

• Following are important catecholamines in the body,

• Dopamine.

• Adrenaline.

• Noradrenaline.

• Tyrosine is the precursor for the synthesis of catecholamines.

• The conversion of tyrosine to catecholamines occurs in adrenal medulla and central nervous system.

• Synthesis of Catecholamines:

• Tyrosine is hydroxylated to 3,4-dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.  

• This reaction requires tetra hydro biopterin as coenzyme.  

• DOPA undergoes PLPdependent decarboxylation to give dopamine which, in turn, is hydroxylated to produce norepinephrine.  

• Methylation of norepinephrine by S-adenosyl methionine gives epinephrine. 

• The difference between epinephrine and norepinephrine is only a methyl group (norepinephrine has no methyl group).

• Functions of catecholamines :

• Norepinephrine and epinephrine regulate carbohydrate and lipid metabolisms.  

• They stimulate the degradation of triacylglycerol and glycogen.  

• They cause an increase in blood pressure.  

• Dopamine and norepinephrine serve as neurotransmitters in the brain and autonomic nervous system.

• Neurotransmitter dopamine plays a role in the brain. 

• Striving, focusing, and finding something interesting rely on it.

• It is associated with pleasure.

Commonly Asked Questions.

1. Write about Synthesis and significance of Catecholamines in the body.

2. Write about Synthesis and significance of Serotonin and Melatonin in the body.

3. Give significance of Serotonin in the body.

4. Give significance of Catecholamines in the body.

5. Give significance of Melatonin in the body.

Catabolism of phenylalanine and tyrosine and associated metabolic disorders.

 

Introduction:

• The aromatic amino acids phenylalanine (Phe) and tyrosine (Tyr) have almost similar structure.

• It is important to consume foods high in phenylalanine. 

• Consuming tyrosine-rich foods, on the other hand, is not required. 

• After being incorporated into proteins, phenylalanine has no other function than to convert to tyrosine. 

• Tyrosine can thus reduce the body's need for phenylalanine. Tyrosine's sparing action on phenylalanine is known as the “sparing action.'

Catabolism of phenylalanine and tyrosine.

• Both phenylalanine and tyrosine metabolism are interconnected and are degraded in the liver by the same pathway.

• The p-hydroxyphenylpyruvate is produced by transamination of tyrosine. 

• Enzyme: Tyrosine transaminase.

• p hydroxyphenylpyruvate is decarboxylated and its phenyl ring is hydroxylated to form homogentisate. Ascorbic acid is needed for this reaction.

• The benzene ring is removed by homogentisate oxidase, resulting in the formation of 4-Maleylacetoacetate. To break an aromatic ring, molecular oxygen is required.

• Maleylacetoacetate is isomerized to 4-fumarylacetoacetate; 

• Enzyme: maleylacetoacetate isomerase.

• Fumarylacetoacetate is hydrolyzed to form Fumarate and acetoacetate. 

• Enzyme: fumarylacetoacetate hydrolase.

• Fumarate is an intermediate in the citric acid cycle and hence gluconeogenic.

• Acetoacetate, which is a ketone body. 

• Hence, tyrosine and phenylalanine are both ketogenic and glucogenic. 

Metabolic disorders:

• Many metabolic disorders are associated with Catabolism of phenylalanine and tyrosine as,

• Phenylketonuria, 

• Albinism, 

• Alkaptonuria,

• Tyrosinemia.

1. Phenylketonuria:

• Phenylketonuria (PKU) is an hereditary metabolic disorder that results in a high level of phenylalanine in the blood.

• The body can accumulate very high levels of phenylalanine which may prove toxic without treatment, resulting in mental retardation and other serious complications. 

• Pregnant women who consume a lot of phenylalanine are more likely to have babies with mental retardation, heart problems, and small heads (microcephaly).

• Their babies are exposed to phenylalanine before birth because it is found in their own blood in very high concentrations.

2. Albinism:

• Both parents carrying the albinism gene have a chance of passing the albinism gene to their child. 

• The cause of albinism is a defect in one of several genes involved in producing and distributing melanin, the pigment responsible for skin, eyes, and hair coloration. 

• Melanin may not be produced or may be produced in very small amounts due to the defect.

• The gene for albinism is inherited from both parents, so a child must have both parents carry the gene. 

• Parents who carry the albinism gene but don't have symptoms are typically carriers of the condition. 

3. Alkaptonuria:

• It's a very rare and hereditary disorder, which causes kidney problems. 

• Caused due to lesser production or total lack of enzyme  homogentisic dioxygenase (HGD). 

• Toxic substances such as homogentisic acid are broken down by this enzyme. 

• Results in high levels of homogentisic acid.

• Symptoms of Alkaptonuria:

• There are dark spots on your eye's sclera (white)

• The cartilage in your ears has thickened and darkened

• Discoloration of your skin, especially in the sweat gland area, that is blue speckled

• Sweat of a dark color or stains of sweat

• Earwax that is black in color

• A urinary stone and a prostate stone

• Knee and hip arthritis (especially)

• Heart problems can also occur as a result of alkaptonuria.

4. Tyrosinemia:

• The body lacks the enzyme [fumarylacetoacetate hydrolase (FAH). 

• A person with tyrosinemia breaks down protein in their bodies in an abnormal way, allowing toxic breakdown products of tyrosine to build up in the body. 

• There is progressive liver damage as well as kidney damage. 

• It's a hereditary disorder.

Commonly Asked Questions.

1. Discuss Catabolism of phenylalanine and tyrosine along with disorders associated with it.

2. Write a short note on,

1. Phenylketonuria, 

2. Albinism, 

3. Alkaptonuria,

4. Tyrosinemia.

Urea Cycle and its Disorders.

 

Introduction:

• Amino acid metabolism produces toxic ammonia which is converted into urea in the liver. 

• Urea cycle takes place in Mitochondria and cytosol of the liver cells. 

• A faulty Urea cycle results in toxic levels of ammonia (NH3) within the body, resulting in many symptoms such as lethargy, incoordination, cerebral edema, and asterixis (neurological disorder that causes a person to lose motor control of certain areas of the body).

Location:

• Mitochondria and cytosol of the liver cells.

Steps of Urea Cycle:

1. Transport of nitrogen to the liver.

2. Reactions of the urea cycle.

1. Transport of nitrogen to the liver:

• Ammonia is very toxic, especially to the CNS.

• The concentration of ammonia and ammonium ions in the blood is normally very low. (NH3 + H+ ↔ NH4+)

• Ammonia travels to the liver from other tissues, mainly in the form of alanine and glutamine.

• It is released from amino acids in the liver by a series of transamination and deamination reactions.

• Ammonia is also produced by bacteria in the gut and travels to the liver via the hepatic portal vein.

2. Reactions of the urea cycle:

• Carbamoyl phosphate is synthesized in the first reaction from NH4+, CO2, and two ATP. Inorganic phosphate and two ADP are also produced.

• Enzyme: carbamoyl phosphate synthetase I, present in mitochondria.

• Ornithine reacts with carbamoyl phosphate to form citrulline. Inorganic phosphate is released.

• Enzyme: ornithine transcarbamylase, located in mitochondria. The product, citrulline, is transported to the cytosol in exchange for cytoplasmic ornithine.

• Citrulline combines with aspartate to form argininosuccinate in a reaction that is driven by the hydrolysis of ATP to AMP and inorganic pyrophosphate.

• Enzyme: Argininosuccinate synthetase

• Argininosuccinate is cleaved to form arginine and fumarate.

• Enzyme: argininosuccinate lyase. This reaction occurs in the cytosol.

• The carbons of fumarate, which are derived from the aspartate added in reaction 3, can be converted to malate.

• In the fasting state in the liver, malate can be converted to glucose or to oxaloacetate, which is transaminated to regenerate the aspartate required for reaction 3.

• Arginine is cleaved to form urea and regenerate ornithine.

• Enzyme: arginase, (located primarily in the liver and is inhibited by ornithine.)

• Urea passes into the blood and is excreted by the kidneys.

• Ornithine is transported back into the mitochondrion (in exchange for citrulline) where it can be used for another round of the cycle.

Important enzymes in Urea Cycle:

1. Carbamoyl phosphate synthetase I: 

1. Converts ammonium and bicarbonate into carbamoyl phosphate. This is the rate-limiting step in the urea cycle. This reaction requires two ATP and occurs in the mitochondria.

2. Ornithine transcarbamylase: 

1. Combines ornithine and carbamoyl phosphate to form citrulline. Located in mitochondria.

3. Argininosuccinate synthetase: 

1. Condenses citrulline with aspartate to form argininosuccinate. This reaction occurs in the cytosol and requires one ATP.

4. Argininosuccinate lyase: 

1. Splits argininosuccinate into arginine and fumarate. Occurs in the cytosol.

5. Arginase: 

1. Cleaves arginine into one molecule of urea and ornithine in the cytosol. The ornithine is then transported back into the mitochondria for entry back into the cycle.

Disorders

• A dysfunctional urea cycle leads to urea cycle disorders, which are congenital diseases. 

• An enzyme deficiency alters the biochemical reactions involved in converting ammonia to urea in the urea cycle, which is subsequently removed via urine. 

• Disorders of the urea cycle are caused by inborn metabolism errors that can lead to brain damage and death in newborns.

Defects in the urea cycle and their consequences

• Symptoms of hyperammonemia occur when the urea cycle enzyme is absent or deficient, which results in an accumulation of ammonia in the body and an elevated blood level of ammonia. 

• When ammonia enters the bloodstream, it damages the brain irreversibly, causing comas and death. 

• Without treatment, children develop physically and mentally slow.

Commonly Asked Questions:

1. With help of a well labeled diagram describing the Urea Cycle.

2. Discuss in detail Urea Cycle and the disorders associated with it.