Amino acids & Aminoacidopathies

Amino acids & Aminoacidopathies

1. AMINO ACIDS HEALTH BIOTECHNOLOGY PREPARED BY : NAHAL JEHANGIR 18006231011 BS.BIOTECHNOLOGY UNIVERSITY OF MANAGEMENT AND TECHNOLOGY.

2. What are AMINO ACIDS ? Amino acids are the building blocks of proteins. The precise amino acid content, and the sequence of those amino acids, of a specific protein is determined by the sequence of the bases in the gene that encodes that protein . The chemical properties of the amino acids of proteins determine the biologic activity of the protein. Proteins catalyze almost all of the reactions in living cells, controlling virtually all cellular processes Growth , repair, and maintenance of all cells are dependent on amino acids .

3. BASIC STRUCTURE OF AMINO ACIDS An amino acid contains at least one of both amino and carboxylic acid functional groups. The N-terminal end amino group (–NH2) and the C-terminal end carboxyl group (–COOH) bond to the alpha-carbon with the amino group of one amino acid linking with the carboxyl group of another, forming a peptide bond . A chain of amino acids is known as a polypeptide , and a large polypeptide constitutes a protein . In human serum, proteins average about 100–150 amino acids in the polypeptide chains. Amino acids differ from one another by the chemical composition of their R group (side chains).

4. GENERAL STRUCTURE OF AMINO ACID

5. PEPTIDE BOND FORMATION A peptide bond is a  chemical  bond formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule, releasing a molecule of  water  (H2O). This is a dehydration synthesis reaction (also known as a condensation reaction), and usually occurs between amino acids.

6. ESSENTIAL /NON-ESSENTIAL AMINO ACIDS ESSENTIAL AMINO ACIDS : About half of the 20 amino acids needed by humans cannot be synthesized at a rapid enough rate to support growth; they must be supplied in food. These nutritionally essential amino acids must be supplied by the diet in the form of proteins . The essential amino acids are arginine (often called semi essential as it is required for the young but not for adults and can be synthesized in high enough amounts that the body needs), histidine , isoleucine, leucine , lysine, methionine, phenylalanine, threonine, tryptophan, and valine .

7. CONT.. NON-ESSENTIAL AMINO ACIDS: The 10 amino acids that the body can produce are alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline , serine, and tyrosine. Tyrosine is produced from phenylalanine, so if the diet is deficient in phenylalanine, tyrosine will be required as well. Humans do not have all the enzymes required for the biosynthesis of all of the amino acids.

8. PRODUCTION OF AMINO ACIDS Under normal circumstances, proteolytic enzymes, such as pepsin and trypsin, completely digest dietary proteins into their constituent amino acids. Amino acids are then rapidly absorbed from the intestine into the blood and subsequently become part of the body’s pool of amino acids . Amino acids are also released by the normal breakdown of body proteins .

9. FUNCTIONS OF AMINO ACIDS The primary purpose of amino acids is for the synthesis of body proteins, including plasma, intracellular, and structural proteins . Amino acids are also used for the synthesis of nonprotein nitrogen-containing compounds such as purines, pyrimidines , porphyrins , creatine , histamine , thyroxine , epinephrine, and the coenzyme NAD. In addition, protein provides 12%–20% of the total daily body energy requirement.

10. CONT… The amino group is removed from amino acids by either deamination or transamination. The resultant ketoacid can enter into a common metabolic pathway with carbohydrates and fats. Glucogenic amino acids generate precursors of glucose, such as pyruvate or a citric acid cycle intermediate. Examples include alanine, which can be deaminated to pyruvate; arginine, which is converted to alpha- ketoglutarate ; and aspartate, which is converted to oxaloacetate. Ketogenic amino acids generate ketone bodies. They are degraded to acetyl-CoA or acetoacetyl -CoA (e.g., leucine or lysine), with some amino acids being both ketogenic and glucogenic . The ammonium ion that is produced during deamination of the amino acids is converted into urea via the urea cycle in the liver.

11. PROPERTIES AND STRUCTURES OF AMINO ACIDS

12. 1. ARGININE ( Arg , R ) Essential amino acid Arginine is a complex amino acid that is often found at the catalytic (active) site in proteins and enzymes due to its amine-containing side chain . Arginine plays an important role in cell division, the healing of wounds, stimulation of protein synthesis, immune function, and the release of hormones . Arginine is required for the generation of urea, which is necessary for the removal of toxic ammonia from the body and is also required for the synthesis of creatine , which degrades to creatinine, a waste product that is cleared from the body by the kidney.

13. 2. HISTIDINE ( His,H ) Essential amino acid Histidine is one of the basic (by pH) amino acids due to its imidazole side chain. It is the direct precursor of histamine, one of the proteins involved in the immune response . Histidine is also an important source of carbon atoms in the synthesis of purines, one of the two groups of nitrogen bases that make up DNA and RNA. Histidine is needed to help grow and repair body tissues and to maintain the myelin sheaths that protect nerve cells. It also helps manufacture red and white blood cells and helps to protect the body from heavy metal toxicity . Histamine stimulates the secretion of the digestive enzyme gastrin and acts as a catalytic site in certain enzymes.

14. 3.ISOLEUCIN ( Ile, I ) Essential amino acid Isoleucine is in the group of branched-chain amino acids that are needed to help maintain, heal, and repair muscle tissue, skin, and bones. Isoleucine is needed for hemoglobin formation, and it helps to regulate blood glucose levels and maintain energy levels.

15. 4. LEUCIN ( Leu , L ) Essential amino acid Leucine is also in the group of branched-chain amino acids, along with valine and isoleucine . Leucine is the second most common amino acid found in protein beside glycine. Leucine , in conjunction with valine and isoleucine, boosts the healing of muscle, skin, and bones; aids in recovery from surgery; and lowers blood glucose levels . Leucine is necessary for the optimal growth of infants and for nitrogen balance in adults.

16. 5. LYSINE ( Lys, K ) Essential amino acid Lysine has a net positive charge, which makes it one of the three basic (by charge) amino acids . Lysine plays a role in the production of antibodies and lowers triglyceride levels. Lysine is needed for proper growth and bone development in children and to maintain a proper nitrogen balance in adults. Lysine helps in the absorption and conservation of calcium and plays an important role in the formation of collagen, a component of cartilage and connective tissue.

17. 6. METHIONINE ( Met, M ) Essential amino acid Methionine is an important amino acid that helps to initiate translation of messenger RNA by being the first amino acid incorporated into the N-terminal position of all proteins . Methionine is a source of sulfur, required by the body for normal metabolism and growth. Methionine assists the breakdown of fats, helps to detoxify lead and other heavy metals, helps diminish muscle weakness, and prevents brittle hair. Methionine reacts with adenosine triphosphate to contribute to the synthesis of many important substances, including epinephrine and choline.

18. 7. PHENYALANINE ( Phe , F ) Essential amino acid Phenylalanine is classified as a nonpolar amino acid because of the hydrophobic nature of its benzyl side chain . It promotes alertness and vitality, elevates mood, decreases pain, aids memory and learning, and is used to treat arthritis and depression . Phenylalanine is used by the brain to produce norepinephrine, a neurotransmitter that transmits signals between nerve cells. Phenylalanine uses an active transport channel to cross the blood-brain barrier and, in large quantities, interferes with the production of serotonin, another neurotransmitter. Phenylalanine is part of the composition of aspartame, a common sweetener used in prepared foods as a sugar replacement. Phenylalanine plays a key role in the biosynthesis of other amino acids.

19. 8. THREONINE ( Thr , T ) Essential amino acid Threonine is an alcohol-containing amino acid that is an important component in the formation of protein, collagen, elastin (a connective tissue protein), and tooth enamel . It is also important in the production of neurotransmitters and health of the nervous system. Threonine helps maintain proper protein balance in the body and it aids liver function, metabolism, and assimilation.

20. 8. TRYPTOPHAN ( Trp , W ) Essential amino acid Tryptophan is formed from proteins during digestion by the action of proteolytic enzymes. Tryptophan is also a precursor for serotonin and melatonin, a neurohormone and powerful antioxidant . Tryptophan is a natural relaxant; it helps alleviate insomnia by inducing sleep, soothes anxiety, and reduces depression. It is used in the treatment of migraine headaches, aids in weight control by reducing appetite, and helps control hyperactivity in children.

21. 9. VALINE ( Val, V ) Essential amino acid Valine is another branched-chain amino acid that is a constituent of fibrous protein in the body. Valine is needed for muscle metabolism and coordination, tissue repair, and maintenance of nitrogen balance. It is used by muscle tissue as an energy source. Valine is used in treatments for muscle, mental, and emotional problems; insomnia; anxiety; and liver and gallbladder disease.

22. 10. ALANINE ( Ala , A ) Non-essential amino acid Alanine is one of the simplest of the amino acids and is involved in the energy-producing breakdown of glucose. Alanine itself is a product of the breakdown of DNA or the dipeptides anserine and carnosine , and the conversion of pyruvate, a pivotal compound in carbohydrate metabolism . Alanine plays a major role in the transfer of nitrogen from peripheral tissue to the liver, helps in reducing the buildup of toxic substances that are released into muscle cells when muscle protein is broken down quickly to meet energy needs, and strengthens the immune system through production of antibodies

23. 11. ASPARAGINE ( Asn , N ) Non-Essential amino acid Asparagine was first isolated in 1806 from asparagus juice, naturally, from where it got its name, becoming the first amino acid to be isolated. Asparagine is one of the principal and frequently the most abundant of the amino acids involved in the transport of nitrogen. Asparagine is the Beta-amide of aspartic acid synthesized from aspartic acid and adenosine triphosphate (ATP ). The main function of asparagine is converting one amino acid into another via amination , the process by which an amine group is introduced into an organic molecule, and transamination, the reaction when an amino acid is transferred to an alpha- ketoacid . Asparagine is required by the nervous system and plays an important role in the synthesis of ammonia

24. 12. ASPARTIC ACID ( Asp, D ) Non-Essential amino acid Aspartic acid is alanine with one of the beta hydrogens replaced by a carboxylic acid group . Aspartic acid plays a vital role in metabolism during construction of other amino acids and metabolites in the citric acid cycle. Among the amino acids that are synthesized from aspartic acid are asparagine, arginine, lysine, methionine, threonine, isoleucine, and several nucleotides . Aspartic acid is also a metabolite in the urea cycle and participates in gluconeogenesis, the generation of glucose from nonsugar carbon substrates.

25. 13. CYSTEIN ( Cys , C ) Cysteine is classified as a nonessential amino acid, but cysteine may be essential for infants, the elderly, and individuals with certain metabolic diseases or malabsorption syndromes. Cysteine is an important structural and functional component of many proteins and enzymes. Cysteine is named after cystine , its oxidized dimer . Cysteine is potentially toxic and is catabolized in the gastrointestinal tract and blood. In opposition, cysteine is absorbed during digestion as cystine , which is more stable in the gastrointestinal tract. It is cystine that travels to cells, where it is reduced to two cysteine molecules upon cell entry. Cysteine is used as a constituent in the food, pharmaceutical, and personal care industries . One of its largest applications is in the production of flavors.

26. 14. GLUTAMIC ACID ( Glu , E ) Non-Essential amino acid Glutamic acid is synthesized from a number of amino acids, and when an amino group is added to glutamic acid, it forms the important amino acid glutamine . Glutamic acid is one of the two amino acids that have a net negative charge (by pH), making it a very polar molecule. Glutamic acid has been linked to epileptic seizures, is a neurotransmitter, is important in the metabolism of sugars and fats, and aids transporting potassium into the spinal fluid. Glutamic acid is present in a wide variety of foods and is responsible for one of the five basic tastes of the human sense of taste (umami). Glutamic acid is often used as a food additive and flavor enhancer in the form of its sodium salt, monosodium glutamate (MSG).

27. 15. GLUTAMINE ( Gln , Q ) Non-Essential amino acid Glutamine is the most abundant amino acid in the body, being involved in more metabolic processes than any other amino acid . Over 61% of skeletal muscle tissue is glutamine. Glutamine is converted to glucose when more glucose is required for energy and aids in immune function. Glutamine assists in maintaining the proper acid/alkaline balance in the body, provides fuel for a healthy digestive tract,6 and is the basis of the building blocks for the synthesis of RNA and DNA. Studies have shown glutamine to be useful in treatment of serious illnesses, injury, trauma, burns, and cancer treatment–related side effects and in wound healing for postoperative patients . Glutamine is also marketed as a supplement used for muscle growth in weightlifting and bodybuilding. Glutamine transports ammonia, the toxic metabolic byproduct of protein breakdown, to the liver, where it is converted into less toxic urea and then excreted by the kidneys.

28. 16. GLYCINE ( Gly , G ) Non-Essential amino acid Glycine is the simplest amino acid synthesized in the body and is the only amino acid that is not optically active because it has no stereoisomers (any of a group of isomers [compounds with the same molecular formula but a different structural formula] in which atoms are linked in the same order but differ in their spatial arrangement). Glycine is essential for the synthesis of nucleic acids, bile acids, proteins, peptides, purines, ATP, porphyrins , hemoglobin, glutathione, creatine , bile salts, glucose, glycogen, and other amino acids. The liver uses glycine to help in the detoxification of compounds and to help in the synthesis of bile acids. Glycine has a sweet taste and is used as a sweetener/taste enhancer. Glycine is an inhibitory neurotransmitter in the central nervous system (CNS), is a metal complexing agent, retards muscle degeneration, improves glycogen storage, and promotes healing.

29. 17. PROLINE ( Pro, P ) Non-Essential amino acid Proline is the precursor of hydroxyproline , which is manufactured into collagen, tendons, ligaments, and heart muscle by the body. Proline is involved in wound healing, plays important roles in molecular recognition, and is an important component in certain medical wound dressings that use collagen to stimulate wound healing. Proline helps in the healing of cartilage and the strengthening of joints, tendons, and heart muscle, and it works with vitamin C to promote healthy connective tissues.

30. 18. SERINE ( Ser , S ) Non-Essential amino acid Serine is the second amino acid that is also an alcohol because of its methyl side chain, which contains a hydroxy group. Serine is needed for the proper metabolism of fats and fatty acids and plays an important role in the body’s synthetic pathways for pyrimidines , purines (making it important for DNA and RNA function), creatine , and porphyrins . It is highly concentrated in all cell membranes, is a component of the protective myelin sheaths surrounding nerve fibers, and aids in the production of immunoglobulins and antibodies for the maintenance of a healthy immune system.

31. 19. TYROSINE ( Tyr, Y ) Non-Essential amino acid Tyrosine is metabolically synthesized from the important amino acid phenylalanine to become the para- hydroxy derivative of phenylalanine. Tyrosine is a precursor of the adrenal hormones epinephrine, norepinephrine, and dopamine and the thyroid hormones, including thyroxine . It is important in overall metabolism, aiding in the functions of the adrenal, thyroid, and pituitary glands. Tyrosine stimulates metabolism and the nervous system, acts as a mood elevator, suppresses the appetite, and helps reduce body fat, making it useful in the treatment of chronic fatigue, narcolepsy, anxiety, depression, low sex drive, allergies, and headaches.

32. AMINO ACIDOPATHIES

33. AMINOACIDOPATHIES Aminoacidopathies are a class of inherited errors of metabolism in which there is an enzyme defect that inhibits the body’s ability to metabolize certain amino acids. The abnormalities exist either in the activity of a specific enzyme in the metabolic pathway or in the membrane transport system for amino acids . Phenylketonuria (PKU ), aminoacidopathy , was the first newborn screening test introduced in the early 1960s. Now , some states require screening tests for up to 26 amino acids.More than 100 diseases have been identified that result from inherited errors of amino acid metabolism. The aminoacidopathy disorders cause severe medical complications due to the buildup of toxic amino acids and/or byproducts of amino acid metabolism in the blood

34. 1. Phenylketonuria Phenylketonuria (PKU) is inherited as an autosomal recessive trait occurs in about 1 in 15,000 births . absence of activity of the enzyme phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine In the absence of the enzyme, phenylalanine levels are usually greater than 1200 micro mol /L.

35. CONT… In the newborn, the upper limit of normal for a phenylalanine level is 120 micro mol /L (2 mg/ dL ). In untreated classic PKU, blood levels as high as 2.4 mM /L can be found . Chronically high levels of phenylalanine and some of its metabolites—e.g., phenylpyruvic acid, phenylpyruvate (also known as phenylketone ), and phenyllactic acid— can cause significant brain problems. All of these compounds are found in both the blood and the urine of a PKU patient, giving the urine a characteristic musty odor. Partial deficiencies of PAH activity are typically classified as mild PKU if phenylalanine levels are between 600–1200 micro mol /L or as non-PKU mild hyperphenylalaninemia if phenylalanine levels are in the range of 180–600 micro mol /L and there is no accompanying accumulation of phenylketones .

36. CONT.. In infants and children with this inherited defect, retarded mental development and microcephaly occur as a result of the toxic effects on the brain of phenylalanine or its metabolic byproducts. Brain damage can be avoided if the disease is detected at birth and the infant is maintained on a diet containing very low levels of phenylalanine. Also , women with PKU who are untreated during pregnancy almost always have babies who are microcephalic and mentally retarded. The fetal effects of maternal PKU are preventable if the mother is maintained on a phenylalanine-restricted diet from before conception through term.

37. 2. Tyrosinemia The inborn metabolic disorders of tyrosine catabolism are characterized by the excretion of tyrosine and tyrosine catabolites in urine . There are three types of tyrosinemia , each with distinctive symptoms and caused by the deficiency of a different enzyme. Type I Type II Type III

38. Type I Tyrosinemia Type I tyrosinemiais the most severe form of this aminoacidopathy and is found in about 1 in 100,000 births. Type I tyrosinemia is caused by low levels of the enzyme fumarylacetoacetate hydrolase , the fifth of five enzymes needed to break down tyrosine . Symptoms of type I tyrosinemia include failure to thrive, diarrhea, vomiting, jaundice, cabbage-like odor, distended abdomen, swelling of legs, and increased predisposition for bleeding. Type I tyrosinemia can lead to liver and kidney failure, problems affecting the nervous system, and an increased risk of cirrhosis or liver cancer later in life.

39. Type II Tyrosinemia Type II tyrosinemia is caused by a deficiency of the enzyme tyrosine aminotransferase . Type II tyrosinemia occurs in fewer than 1 in 250,000 births. Tyrosine aminotransferase is the first in a series of five enzymes that converts tyrosine to smaller molecules, which are excreted by the kidneys or used in energy producing reactions. About half of individuals with type II tyrosinemia are mentally retarded and have symptoms of excessive tearing, photophobia (abnormal sensitivity to light), eye pain and redness, and painful skin lesions on the palms and soles of the feet.

40. Type III Tyrosinemia Type III tyrosinemia is a rare disorder (only a few cases have been reported) caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase . This enzyme is found mainly in the liver with lesser amounts found in the kidneys. It , too, is one of the series of enzymes needed to break down tyrosine. The clinical picture of type III tyrosinemia patients includes mild mental retardation, seizures, and periodic loss of balance and coordination.

41. 3. Alkaptonuria Alkaptonuria is an inborn metabolic disease transmitted as an autosomal recessive gene, the HGD gene which causes the lack of the enzyme homogentisate oxidase, which is needed in the metabolism of tyrosine and phenylalanine. This disorder occurs in about 1 of 250,000 births. A predominant clinical manifestation of alkaptonuria is that the patient’s urine turns brownish-black when it mixes with air. This phenomenon is due to an accumulation in the urine of homogentisic acid (HGA), which oxidizes to produce this dark pigment.

42. CONT.. Alkaptonuric patients have no immediate problems; however, late in the disease, the high level of HGA gradually accumulates in connective tissue, causing ochronosis (pigmentation of these tissues), an arthritis-like degeneration from the buildup of homogentisic acid in the cartilage, dark spots on the sclera (white of the eye), and deposition of pigment in the cartilage of the ears, nose, and tendons of the extremities. Urinalysis is done to test for alkaptonuria . When ferric chloride is added to the urine, it will turn the urine black in patients with alkaptonuria . Treatment for alkaptonuria is high-dose vitamin C, which has been shown to decrease the buildup of brown pigment in the cartilage and may slow the development of arthritis.

43. 4. MAPLE SYRUP URINE DISEASE Maple syrup urine disease (MSUD) results from an absence or greatly reduced activity of the enzyme branched-chain alpha- ketoacid decarboxylase blocking the normal metabolism of the three essential branched-chain amino acids leucine , isoleucine, and valine . MSUD is an autosomal recessive genetic inherited disorder. Newborn screening for MSUD has been part of several state screening programs since the mid-1970s with a reported prevalence of 1 in 150,000 births in the general population. The most striking feature of this hereditary disease is the characteristic maple syrup or burnt sugar odor of the urine, breath, and skin. The result of this enzyme defect is an accumulation of the branched-chain amino acids and their corresponding ketoacids in the blood, urine, and cerebrospinal fluid (CSF).

44. 5. ISOVALERIC ACIDEMIA Isovaleric acidemia is an autosomal recessive metabolic disorder from a deficiency of the enzyme isovaleryl -CoA dehydrogenase preventing normal metabolism of the branched-chain amino acid leucine . The prevalence of Isovaleric acidemia is approximately 1 in 250,000 births in the United States, caused by mutations in the isovalerylCoA dehydrogenase (IVD) gene .

45. CONT.. A characteristic feature of isovaleric acidemia is a distinctive odor of sweaty feet caused by the buildup of isovaleric acid. Health problems related to isovaleric acidemia range from very mild to life-threatening, but when severe, it can damage the brain and nervous system. Clinical manifestations of this disorder become apparent a few days after birth and include failure to thrive, vomiting, and lethargy that can progress to seizures, coma, and possibly death. Some people with gene mutations that cause isovaleric acidemia are asymptomatic and never experience any signs and symptoms of the condition.

46. 6. HOMOCYSTINURIA Homocystinuria is yet another inherited autosomal recessive disorder of amino acid metablolism . it is the lack of the enzyme cystathionine -beta synthetase , necessary for the metabolism of the amino acid methionine results in elevated plasma and urine levels of methionine and of the precursor homocysteine . The incidence of this disease is about 1 in 200,000 births. Infants seem to be healthy, and early symptoms, if any, are indistinct. Associated clinical findings in late childhood include osteoporosis, dislocated lenses in the eye resulting from the lack of cysteine synthesis essential for collagen formation, and, frequently, mental retardation. This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, thinning and weakening of bones, and thrombosis resulting from the toxicity of homocysteine to the vascular endothelium if it goes untreated.

47. METHIONINE HOMOCYSTEIN CYSTATHIONINE

48. 7. CYSTINURIA Cystinuria is an inherited autosomal recessive defect caused by a defect in the amino acid transport system rather than a metabolic enzyme deficiency. Cystinuria is characterized by the inadequate reabsorption of cystine during the filtering process in the kidneys resulting in an excessive concentration of this amino acid. Cystine precipitates out of the urine and forms stones in the kidneys, ureters, or bladder. The kidney stones often recur throughout a patient’s lifetime and are directly or indirectly responsible for all of the signs and symptoms of the disease, including hematuria, pain in the side due to kidney pain, and urinary tract infections.

49. Sr. No Disorder name Amino acid Enzyme absent Disease ratio 1 Phenylketonuria (PKU) phenylalanine phenylalanine hydroxylase (PAH) 1 in 15,000 births 2 Tyrosinemia ( has 3 types)         Type I tyrosinemia phenylalanine fumarylacetoacetate hydrolase 1 in 100,000 births.   Type II tyrosinemia tyrosine Tyrosine aminotransferase 1 in 250,000 births.   Type III tyrosinemia p- OHphenylpyruvate 4-hydroxyphenylpyruvate dioxygenase Rare disorder 3 Alkaptonuria homogentisic acid homogentisate oxidase 1 of 250,000 births 4   Maple syrup urine disease (MSUD) Not mentioned in book alpha-ketoacid decarboxylase 1 in 150,000 births 5 Isovaleric Acidemia Not mentioned in book isovaleryl -CoA dehydrogenase 1 in 250,000 births 6 Homocystinuria Homocysteine (Hcy) cystathionine-beta synthetase 1 in 200,000 births