Amino Acid Biosynthesis & Degradation Learning Objectives : 1. Know the groups of a.a. biosynthetic families 2. The enzymes and coenzymes involved in the synthetic pathways 3. The enzyme deficiencies of each pathway. 4. The consequences of the inborn errors of metabolism

Amino Acid Biosynthetic Families, Grouped by Metabolic Precursor α-Ketoglutarate Pyruvate Glutamate Alanine Glutamine Valine* Proline Leucine* Arginine Isoleucine* 3-Phosphoglycerate Phosphoenolpyruvate and Serine erythrose 4-phosphate Glycine Tryptophan* Cysteine Phenylalanine* Oxaloacetate Tyrosine Aspartate Ribose 5-phosphate Aspargine Histidine* Methionine* Threonine* Lysine*

Biosynthetic Families of Amino Acids in Bacteria and Plants

Pyruvate as an Entry Point into Metabolism Pyruvate is the entry point of the three-carbon amino acids alanine, serine, and cysteine into the metabolic mainstream The transamination of alanine directly yields pyruvate. Glutamate is then oxidatively deaminated, yielding NH4+ and regenerating α-ketoglutarate. The sum of these reactions is

Another simple reaction in the degradation of amino acids is the deamination of serine to pyruvate by serine dehydratase

Methionine Metabolism

Activated Methyl Cycle Activated Methyl Cycle. The methyl group of methionine is activated by the formation of Sadenosylmethionine

Oxygenases Are Required for the Degradation of Aromatic Amino Acids The degradation of phenylalanine begins with its hydroxylation to tyrosine, a reaction catalyzed by phenylalanine hydroxylase. This enzyme is called a monooxygenase (or mixed-function oxygenase) because one atom of O2 appears in the product and the other in H2O.

Phenylalanine & Tyrosine Degradation

Phenylalanine Catabolism Is Genetically Defective in Some People Genetic defects of amino acid metabolism can cause defective neural development and mental retardation. In most such diseases specific intermediates accumulate. For example, a genetic defect in phenylalanine hydroxylase, The first enzyme in the catabolic pathway for phenylalanine , is responsible for the disease phenylketonuria (PKU), the most common cause of elevated levels of phenylalanine (hyperphenylalaninemia).

The incidence of phenylketonuria is about 1 in 20,000 newborns The incidence of phenylketonuria is about 1 in 20,000 newborns. The disease is inherited in an autosomal recessive manner. Heterozygotes, who make up about 1.5% of a typical population, appear normal. Carriers of the phenylketonuria gene have a reduced level of phenylalanine hydroxylase, as indicated by an increased level of phenylalanine in the blood

Because the major outflow pathway is blocked in phenylketonuria, the blood level of phenylalanine is typically at least 20-fold as high as in normal people. Minor fates of phenylalanine in normal people, such as the formation of phenylpyruvate, become major fates in phenylketonurics.

Alcaptonuria is an inherited metabolic disorder caused by the absence of homogentisate oxidase.

The Branched-Chain Amino Acids Yield Acetyl CoA, Acetoacetate, or Propionyl CoA The degradative pathways of valine and isoleucine resemble that of leucine. After transamination and oxidative decarboxylation to yield a CoA derivative, the subsequent reactions are like those of fatty acid oxidation. Isoleucine yields acetyl CoA and propionyl CoA, whereas valine yields CO2 and propionyl CoA.

Tryptophan Degradation Tryptophan Degradation. The pathway for the conversion of tryptophan into alanine and acetoacetate

Histidine Degradation Conversion of histidine into glutamate Glutamate Formation. Conversion of proline and arginine into glutamate

Succinyl CoA Formation Succinyl CoA Formation. Conversion of methionine, isoleucine, and valine into succinyl CoA

Some Human Genetic Disorders Affecting Amino Acid Catabolism Medical condition Defective process Defective enzyme Symptoms and effects Albinism Melanin synthesis from tyrosine Tyrosine 3-monooxygenase (Tyrosinase) Lack of pigmentation: white hair, pink skin Alkaptonuria Tyrosine degradation Homogentisate 1,2-dioxygenase Dark colour of urine; late developing Arthritis Argininemia Urea synthesis Arginase Mental retardation

Medical condition Defective process Defective enzyme Symptoms and effects Carbamoyl phosphate synthetase I deficiency Urea synthesis Carbamoyl phosphatase I Lethargy; convulsions; early death Homocystinuria Methionine degradation Cystathionine –β synthase Faulty bone development; mental retardation Maple syrup urine disease (branched- chain ketoaciduria) Isoleucine, leucine, & Valine degradation Branched-chain –α keto acid dehydrogenase complex Vomiting; convulsions mental retardation, early death

Medical condition Defective process Defective enzyme Symptoms and effects Methylmalonic acidemia Conversion of propionyl-CoA to succinyl-CoA Methylmalonyl-CoA mutase Vomiting; convulsions; mental retardation; Early death Phenylketonuria Conversion of phenylalanine to tyrosine Phenylalanine hydroxylase Neonatal vomiting Mental retardation

Inherited defects of a. a. met Inherited defects of a.a. met. almost result in mental retardation or other developmental abnormalities as a result of harmful accumulation of metabolites .

END of PROTEIN METABOLISM