Synthesis and degradation of Amino acids

The catabolism of the amino acids involves: Overview The catabolism of the amino acids involves: Removal of α-amino groups. Breakdown of the resulting carbon skeletons. The resulting compounds will be used to form seven intermediate products: oxaloacetate, α-ketoglutarate, pyruvate, fumarate, succinyl coenzyme A (CoA), acetyl CoA, and acetoacetate. These products directly enter the pathways of intermediary metabolism, resulting either in the synthesis of glucose or lipid or in the production of energy through their oxidation to CO2 and water by the Krebs cycle.

Fates of the Carbon Skeletons of Amino Acids Fates of the Carbon Skeletons of Amino Acids. Glucogenic amino acids are shaded red, and ketogenic amino acids are shaded blue. Most amino acids are both glucogenic and ketogenic.

Essential amino acids in humans Lysine Methionine Threonine Phenylalanine Tryptophan Arginine* Histidine* Isoleucine Leucine Valine *Required to some degree in young growing period and/or sometimes during illness.

Non-essential amino acids in humans Can be formed from a-keto acids by transamination and subsequent reactions. Alanine Asparagine Aspartate Glutamate Glutamine Glycine Proline Serine Cysteine (from Met*) Tyrosine (from Phe*) * Essential amino acids

Metabolic relationship of amino acids BODY PROTEINS Proteosynthesis Degradation AMINO ACIDS DIETARY PROTEINS GLYCOLYSIS KREBS CYCLE Digestion Transamination NONPROTEIN DERIVATIVES Porphyrins Purines Pyrimidines Neurotransmitters Hormones Komplex lipids Aminosugars UREA NH3 (Carbon skeleton) Conversion 250 – 300 g/day ACETYL CoA GLUCOSE CO2 KETONBODIES

Biosynthesis of amino acids :transamination reactions All amino acids except threonine, lysine, and proline can be transaminated amino acid1 +a-keto acid2 amino acid2 +a-keto acid1 Keto-acid + Glutamate Pyridoxal phosphate (PLP)- dependent aminotransferase + Amino acid a-Ketoglutarate

Clinicaly important transaminases Alanine-a-ketoglutarate transferase ALT (also called glutamate-pyruvate transaminase – GPT) Aspartate-a-ketoglutarate transferase AST (also called glutamate-oxalacetate transferase – GOT) Important in the diagnosis of heart and liver damage caused by heart attack, drug toxicity, or infection. ALT

Glucose-alanine cycle Alanine plays a special role in transporting amino groups to liver. Ala is the carrier of ammonia and of the carbon skeleton of pyruvate from muscle to liver. The ammonia is excreted and the pyruvate is used to produce glucose, which is returned to the muscle.

Glucogenic Amino Acids formed: a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl-CoA Aspartate Asparagine Arginine Proline Methionine Valine Glutamine Glutamate Threonine Alanine Serine Cysteine Glycine Histidine

formed acetyl CoA or acetoacetate Ketogenic Amino Acids formed acetyl CoA or acetoacetate Lysine Leucine

Both glucogenic and ketogenic amino acids formed: a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl-CoA in addition to acetyl CoA or acetoacetate Isoleucine Tryptophan Phenylalanine Tyrosine

The C3 family: alanine, serine, cysteine and threonine are converted to pyruvate

The C4 family: aspartate and asparagine are converted into oxalacetate Aspartic acid Asparagine Oxalacetate

The C5 family: several amino acids are converted into a-ketoglutarate through glutamate Glutamine a-ketoglutarate Proline Arginine Histidine

Interconversion of amino acids and intermediates of carbohydrate metabolism and Krebs cycle

Synthesis of Ala, Val, and Lue —Ala, Val, and Lue are derived from pyruvate （EMP） carbon skeleton

Synthesis of Ser, Gly and Cys —Ser, Gly, and Cys are derived from 3-phosphoglycerate（EMP） carbon skeleton

Synthesis of Glu, Gln, Pro and Arg —α-Ketoglutarate （TCA） gives rise to Glu, Gln, Pro, and Arg synthesis carbon skeleton

—Oxaloacetate（TCA） gives rise to Asp, Asn, Met, Lys, Thr synthesis Synthesis of Asp, Asn, Met, Lys,Thr and Arg —Oxaloacetate（TCA） gives rise to Asp, Asn, Met, Lys, Thr synthesis carbon skeleton

Synthesis of His carbon skeleton

Diseases related to the amino acid metabolism

Role of homocysteine in vascular disease There is a not a proven cause and effect relationship of elevated homocysteine with cardiovascular disease. Elevated plasma homocysteine levels are an independent cardiovascular risk factor that correlates with the severity of coronary artery disease. Dietary supplementation with folate, vitamin B12 and vitamin B6 the three vitamins involved in the metabolism of homocysteine to a reduction in circulating levels of homocysteine.

Deficiency of phenylalanine hydroxylase (common) or deficiencies in the enzymes that synthesize or reduce the coenzyme BH4. Elevated levels of phenylalanine, phenyl- lactate, phenylpyruvate in plasma and urine  characteristic mousey odor of urine. Phenyl ketouria CNS symptoms: Mental retardation, failure to walk or talk, seizures, hyperactivity, tremor Hypopigmentation: deficiency of pigmentation (fair hair, light skin color, and blue eyes) < hydroxylation of tyrosine by tyrosinase, which is the first step in the formation of the pigment melanin

Phenyl ketouria Neonatal diagnosis of PKU : laboratory testing for elevated blood levels of phenylalanine is mandatory However, fetus at birth  normal level of phenyl-alanine (mother)  tests performed at birth may show false negative results  exposure of new born to protein diet 24 h after birth  better results. Treatment of PKU: feeding synthetic amino acid preparations low in phenylalanine, supplemented with some natural foods Maternal PKU : When mother suffering from PKU + high level on phenylanaline  microcephaly, mental retardation, and congenital heart abnormalities in the fetus Dietary control of blood phenylalanine prior to conception, and must be maintained throughout the pregnancy

which is oxidized to a dark pigment on standing Alkaptonuria A rare metabolic disease involving a deficiency in homogentisic homogentisic tyrosine) Characteristic acid oxidase acid  accumulation (degenerative pathway of symptoms: homogentisic aciduria which is oxidized to a dark pigment on standing large joint arthritis and black pigmentation of cartilage and collagenous tissue Patients are without symptoms till 40 Diets low in protein may help

Albinism A group of conditions with a defect in tyrosine metabolism  a deficiency in the production of melanin  partial or full absence of pigment from the skin, hair, and eyes. Oculo-cutaneous albinism: due to a deficiency of tyrosinase activity, causing a total absence of pigment from the hair, eyes, and skin  The most severe form of the condition. Affected people may appear to have white hair, skin, and photophobia (sunlight is painful to their eyes), they sunburn easily, and do not tan.