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Chapter 21:Summary Malonyl-CoA is an important precursor for biosynthesis of fatty acids Fatty acid synthesis is carried out by a large enzyme that contains multiple catalytic activities needed for the condensation, and subsequent reduction of acetate units Not all organisms can synthesize polyunsaturated fatty acids; these that can utilize mixed function oxidases as desaturase Cholesterol biosynthesis starts with synthesis of mevalonate from acetate; mevalonate yields two activated isoprenes; series of isoprene condensation steps gives squalene; oxidation and ring closure of squalene gives cholesterol In this chapter, we learned that:
CHAPTER 18 Amino Acid Oxidation Production of Urea –How proteins are digested in animals –How amino acids are degraded in animals –How urea is made in made and excreted Key topics:
Oxidation of Amino Acids is a Significant Energy-Yielding Pathway in Carnivores Not all organisms use amino acids as the source of energy About 90% of energy needs of carnivores can be met by amino acids immediately after a meal Only a small fraction of energy needs of herbivores are met by amino acids Microorganisms scavenge amino acids from their environment for fuel
The cute herbivores, again
Metabolic Circumstances of Amino Acid Oxidation Amino acids undergo oxidative catabolism under three circumstances: –Leftover amino acids from normal protein turnover are degraded –Dietary amino acids that exceed body’s protein synthesis needs are degraded –Proteins in the body are broken down to supply amino acids for catabolism when carbohydrates are in short supply (starvation, diabetes mellitus),
Dietary Proteins are Enzymatically Hydrolyzed Pepsin cuts protein into peptides in the stomach Trypsin and chymotrypsin cut proteins and larger peptides into smaller peptides in the small intestine Aminopeptidase and carboxypeptidases A and B degrade peptides into amino acids in the small intestine
Enzymatic Degradation of Dietary Proteins
Part of the human digestive (gastrointestinal) tract. (a) The parietal cells and chief cells of the gastric glands secrete their products in response to the hormone gastrin. Pepsin begins the process of protein degradation in the stomach. (b) The cytoplasm of exocrine cells is completely filled with rough endoplasmic reticulum, the site of synthesis of the zymogens of many digestive enzymes. The collecting ducts ultimately lead to the pancreatic duct and thence to the small intestine. (c) Amino acids are absorbed through the epithelial cell layer (intestinal mucosa) of the villi and enter the capillaries. Recall that the products of lipid hydrolysis in the small intestine enter the lymphatic system after their absorption by the intestinal mucosa.
Overview of Amino Acid Catabolism The amino groups and the carbon skeleton take separate but interconnected pathways
The Amino Group is Removed From All Amino Acids First
Fates of Nitrogen in Organisms Plants conserve almost all the nitrogen Many aquatic vertebrates release ammonia to their environment –Passive diffusion from epithelial cells –Active transport via gills Many terrestrial vertebrates and sharks excrete nitrogen in the form of urea –Urea is far less toxic that ammonia –Urea has very high solubility Some animals, such as birds and reptiles excrete nitrogen as uric acid –Uric acid is rather insoluble –Excretion as paste allows to conserve water Humans and great apes excrete both urea (from amino acids) and uric acid (from purines)
Excretory Forms of Nitrogen
Enzymatic Transamination All aminotransferases rely on the pyridoxal phosphate cofactor Typically, -ketoglutarate accepts amino groups L-Glutamine acts as a temporary storage of nitrogen L-Glutamine can donate the amino group when needed for amino acid biosynthesis
Enzyme-catalyzed transaminations In many aminotransferase reactions, α- ketoglutarate is the amino group acceptor. All aminotransferases have pyridoxal phosphate (PLP) as cofactor. Although the reaction is shown here in the direction of transfer of the amino group to α-ketoglutarate, it is readily reversible
Structure of Pyridoxal Phosphate and Pyridoxamine Phosphate Intermediate, enzyme-bound carrier of amino groups Aldehyde form can react reversibly with amino groups Aminated form can react reversibly with carbonyl groups
Pyridoxal phosphate, the prosthetic group of aminotransferases
Pyridoxal Phosphate is Covalently Linked to the Enzyme In the Resting Enzyme The linkage is made via an nucleophilic attack of the amino group an active-site lysine side chain After dehydration, a Schiff base linkage is formed The covalent complex is called internal aldimine because the Schiff base connects PLP to the enzyme
Pyridoxal phosphate is bound to the enzyme through noncovalent interactions and a Schiff-base (aldimine) linkage to a Lys residue at the active site.
PLP (red) bound to one of the two active sites of the dimeric enzyme aspartate aminotransferase, a typical aminotransferase
PLP (red, with yellow phosphorus) in aldimine linkage with the side chain of Lys258 (purple)
Chemistry of the Amino Group Removal by the Internal Aldimine The external aldimine of PLP is a good electron sink, allowing removal of -hydrogen
Some amino acid transformations at the α carbon that are facilitated by pyridoxal phosphate To complete the process, a second α-keto acid replaces the one that is released, and this is converted to an amino acid in a reversal of the reaction steps (right to left). This activated form of PLP readily undergoes transimination to form a new Schiff base (external aldimine) with the α-amino group of the substrate amino acid.
PLP Also Catalyzes Racemization of Amino Acids
PLP Also Catalyzes Decarboxylation of Amino Acids
Ammonia in Transported in the Bloodstream Safely as Glutamate Un-needed glutamine is processed in intestines, kidneys and liver
Glutamate can Donate Ammonia to Pyruvate to Make Alanine Vigorously working muscles operate nearly anaerobically and rely on glycolysis for energy Glycolysis yields pyruvate that muscles cannot metabolize aerobically; if not eliminated lactic acid will build up This pyruvate can be converted to alanine for transport into liver
Ammonia transport in the form of glutamine.
Excess Glutamate is Metabolized in the Mitochondria of Hepatocytes
Reactions that feed amino groups into the urea cycle
The Glutamate Dehydrogenase Reaction Two-electron oxidation of glutamate followed by hydrolysis Net process is oxidative deamination of glutamate Occurs in mitochondrial matrix in mammals Can use either NAD + or NADP + as electron acceptor
Reaction catalyzed by glutamate dehydrogenase. The glutamate dehydrogenase of mammalian liver has the unusual capacity to use either NAD+ or NADP+ as cofactor. The glutamate DHs of plants and microorganisms are generally specific for one or the other. The mammalian enzyme is allosterically regulated by GTP and ADP.
Ammonia is Re-captured via Synthesis of Carbamoyl Phosphate This is the first nitrogen-acquiring reaction
Nitrogen-acquiring reactions in the synthesis of urea. This reaction has two activation steps (1 and 3). Nitrogen from Carbamoyl Phosphate Enters the Urea Cycle
Urea cycle and reactions that feed amino groups into the cycle
Entry of Aspartate into the Urea Cycle This is the second nitrogen-acquiring reaction
Nitrogen-acquiring reactions in the synthesis of urea. In the reaction catalyzed by argininosuccinate synthetase, the second nitrogen enters from aspartate. Activation of the ureido oxygen of citrulline in step 1 sets up the addition of aspartate in step 2.
Not All Amino Acids can be Synthesized in Humans These amino acids must be obtained as dietary protein Consumption of a variety of foods (including vegetarian only diets) well supplies all the essential amino acids
Fate of Individual Amino Acids Seven to acetyl-CoA –Leu, Ile, Thr, Lys, Phe, Tyr, Trp Six to pyruvate –Ala, Cys, Gly, Ser, Thr, Trp Five to -ketoglutarate –Arg, Glu, Gln, His, Pro Four to succinyl-CoA –Ile, Met, Thr, Val Two to fumarate –Phe, Tyr Two to oxaloacetate –Asp, Asn
Summary of Amino Acid Catabolism
Some enzyme cofactors important in one-carbon transfer reactions
Conversions of one-carbon units on tetrahydrofolate
Synthesis of methionine and S-adenosylmethionine in an activated-methyl cycle
Catabolic pathways for alanine, glycine, serine, cysteine, tryptophan, and threonine
Interplay of the pyridoxal phosphate and tetrahydrofolate cofactors in serine and glycine metabolism
Catabolic pathways for tryptophan, lysine, phenylalanine, tyrosine, leucine, and isoleucine.
Tryptophan as precursor
Catabolic pathways for phenylalanine and tyrosine. In humans these amino acids are normally converted to acetoacetyl-CoA and fumarate. Genetic defects in many of these enzymes cause inheritable human diseases.
Role of tetrahydrobiopterin in the phenylalanine hydroxylase reaction. The H atom shaded pink is transferred directly from C-4 to C-3 in the reaction. This feature, discovered at the National Institutes of Health, is called the NIH shift.
In PKU, phenylpyruvate accumulates in the tissues, blood, and urine. The urine may also contain phenylacetate and phenyllactate.
Catabolic pathways for arginine, histidine, glutamate, glutamine, and proline
Catabolic pathways for methionine, isoleucine, threonine, and valine.
Catabolic pathways for the three branchedchain amino acids: valine, isoleucine, and leucine. All three pathways occur in extrahepatic tissues and share the first two enzymes, as shown here. The branched-chain α-keto acid dehydrogenase complex is analogous to the pyruvate and α-ketoglutarate dehydrogenase complexes.This enzyme is defective in people with maple syrup urine disease.
Catabolic pathway for asparagine and aspartate
Chapter 18: Summary Amino acids from protein are an important energy source in carnivorous animals Catabolism of amino acids involves transfer of the amino group via PLP-dependent aminotransferase to a donor such as -ketoglutarate to yield L-glutamine L-glutamine can be used to synthesize new amino acids, or it can dispose of excess nitrogen as ammonia In most mammals, toxic ammonia is quickly recaptured into carbamoyl phosphate and passed into the urea cycle In this chapter, we learned that: