principles of biochemistry fourth edition chapter 17 amino acid metabolism copyright © 2006 pearson...
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Principles of BiochemistryFourth Edition
Chapter 17Amino Acid Metabolism
Copyright © 2006 Pearson Prentice Hall, Inc.
Horton • Moran • Scrimgeour • Perry • Rawn
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Chapter 17 - Amino Acid Metabolism
• Metabolism of the 20 common amino acids is considered from the origins and fates of their:
(1) Nitrogen atoms (2) Carbon skeletons
• For mammals: Essential amino acids must be obtained from diet
Nonessential amino acids - can be synthesized
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17.1 The Nitrogen Cycle and Nitrogen Fixation
• Nitrogen is needed for amino acids, nucleotides
• Atmospheric N2 is the ultimate source of biological nitrogen
• Nitrogen fixation: a few bacteria possess nitrogenase which can reduce N2 to ammonia
• Nitrogen is recycled in nature through the nitrogen cycle
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Fig 17.1 The Nitrogen cycle
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Nitrogen Fixation
• Most green plants and some microorganisms contain nitrate reductase and nitrite reductase, enzymes that together catalyze the reduction of nitrogen oxides to ammonina.
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Nitrogenase
• An enzyme present in Rhizobium bacteria that live in root nodules of leguminous plants
• Some free-living soil and aquatic bacteria also possess nitrogenase
• Nitrogenase reaction:
N2 + 8 H+ + 8 e- + 16 ATP
2 NH3 + H2 + 16 ATP + 16 Pi
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17.2 Assimilation of Ammonia
• Ammonia generated from N2 is assimilated into low molecular weight metabolites such as glutamate or glutamine
• At pH 7 ammonium ion predominates (NH4+)
• At enzyme reactive centers unprotonated NH3 is the nucleophilic reactive species
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A. Ammonia Is Incorporated into Glutamate
• Reductive amination of -ketoglutarate by glutamate dehydrogenase occurs in plants, animals and microorganisms
• Glutamine is a nitrogen donor in many biosynthetic reactions
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Fig 17.5 Glutamate synthase catalyze the reductive amination of -ketoglutarate
• Animals do not have glutamate synthase.
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B. Transamination Reactions
• Transfer of an amino group from an -amino acid to an -keto acid
• In amino acid biosynthesis, the amino group of glutamate is transferred to various -keto acids generating -amino acids
• In amino acid catabolism, transamination reactions generate glutamate or aspartate
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Fig 17.6 Transfer of an amino group from an -amino acid to an -keto acid
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Fig 17.7 Pig (Sus scrofa) cytosolic aspartate transaminase
(Space-filling model: the coenzyme pyridoxal phosphate)
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Fig 17.8 Assimilation of ammonia into amino acids
a. The glutamate dehydrogenase pathway.
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Fig 17.8 Assimilation of ammonia into amino acids
b. Combined action of glutamine synthetase and glutamate synthase under conditions of low NH4
+ concentration.
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17.3 Synthesis of Amino Acids
• Most bacteria and plants (not mammals) synthesize all 20 common amino acids
• Nonessential amino acids for mammals are usually derived from intermediates of glycolysis or the citric acid cycle (11 of the 20 a.a.)
• Amino acids with the largest energy requirements are usually essential amino acids
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Box 17.3 Essential and Nonessential Amino Acids in Animals
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Fig 17.9 Biosynthesis of Amino Acids
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A. Asparate and Asparagine
• Oxaloacetate is the amino-group acceptor in a transamination reaction that produces asparate.
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B. Lysine, Methionine, and Threonine
• Aspartate is the precursor of lysine, methionine, and threonine.
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C. Alanine, Valine, Leucine, and Isoleucine
• Pyruvate is the amino group acceptor in the synthesis of alanine by a transamination reaction.
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C. Alanine, Valine, Leucine, and Isoleucine• Pyruvate is also a precursor in the synthesis of the
branched-chain amino acids valine, leucine, and isoleucine.
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D. Glutamate, Glutamine, Arginine, and Proline
Fig 17.13 Conversion of glutamate to proline and arginine
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E. Serine, Glycine, and Cysteine
• Serine, glycine, and cysteine- are derived from the glycolytic/gluconeogenic intermediate 3-phosphoglycerate.
Fig 17.14 Biosynthesis of serine.
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E. Serine, Glycine, and Cysteine
• Serine, glycine, and cysteine- are derived from the glycolytic/gluconeogenic intermediate 3-phosphoglycerate.
Fig 17.15 Biosynthesis of glycine.
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E. Serine, Glycine, and Cysteine
• Serine, glycine, and cysteine- are derived from the glycolytic/gluconeogenic intermediate 3-phosphoglycerate.
Fig 17.16 Biosynthesis of cysteine from serine in many bactera and plants.
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Fig 17.17 Biosynthesis of cysteine in mammals
• Animals do not have the normal cysteine biosynthesis pathway shown in fig 17.16.
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F. Phenylalanine, Tyrosine, and Tryptophan• Chorismate, a derivative of shikimate, is a key branch-point
intermediate in aromatic amino acid synthesis.• Animals can not synthesize chorismate.
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Fig 17.19 Biosynthesis of phenylalanine and tyrosine from chorismate in E. coli
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Indole glycerol phosphate for Trp biosynthesis
• Anthranilate is produced from chorismate
• Anthranilate is then converted into indole glycerol phosphate for Trp synthesis
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Fig 17.21 Reactions catalyzed by tryptophan synthase
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G. Histidine
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17.4 Amino Acids as Metabolic Precursors
• The primary role of amino acids is to serve as substances for protein synthesis.
• Some amino acids are essential precursors in other biosynthesis pathways.– Glutamate, glutamine, and asparate
• Required in the urea cycle• Involved in many transamination• Purine and pyrimidine biosynthesis
– Serine and glycine (Fig 17.23)– Arginine (Fig 17.24)
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Fig 17.23 Compounds formed from serine and glycine
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Synthesis of Nitric Oxide (NO) from Arginine
• Nitric oxide (.N=O) is a gas which can diffuse rapidly into cells, and is a messenger that activates guanylyl cyclase (GMP synthesis)
• NO relaxes blood vessels, lowers blood pressure, and is a neurotransmitter in the brain (high levels of NO during a stroke kill neurons)
• Nitroglycerin is converted to NO and dilates coronary arteries in treating angina pectoris
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Fig 17.24 Conversion of arginine to nitric oxide and citrulline
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Sidenafil citrate is the active ingredient in Viagra®
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17.5 Protein Turnover
• Proteins are continuously synthesized and degraded (turnover) (half-lives minutes to weeks)
• Lysosomal hydrolysis degrades some proteins
• Some proteins are targeted for degradation by a covalent attachment (through lysine residues) of ubiquitin (C terminus)
• Proteasome hydrolyzes ubiquitinated proteins
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Fig 17.25 Ubiquitination and hydrolysis of a protein
• Ubiquination enzymes attach multiple ubiquitins
• Proteasome hydrolyzes uniquinated proteins
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17.6 Amino Acid Catabolism
• Amino acids from degraded proteins or from diet can be used for the biosynthesis of new proteins
• During starvation proteins are degraded to amino acids to support glucose formation
• First step is often removal of the -amino group
• Carbon chains are altered for entry into central pathways of carbon metabolism
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Catabolism of the Carbon Chains of Amino Acids
• After removal of amino groups, carbon chains of the 20 amino acids can be degraded
• Degradation products:
Citric acid cycle intermediates
Pyruvate
Acetyl CoA or acetoacetate
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Catabolism of Carbon Skeletons
• Fig 17.26 (next slide)
• Conversion of the carbon skeletons of amino acids to:
Pyruvate
Acetoacetate
Acetyl CoA
Citric acid cycle intermediates
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Glucogenic vs Ketogenic Amino Acids
• Glucogenic amino acids can supply gluconeogenesis pathway via pyruvate or citric acid cycle intermediates
• Ketogenic amino acids can contribute to synthesis of fatty acids or ketone bodies
• Some amino acids are both glucogenic and ketogenic
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A. Alanine, Asparagine, Aspartate, Glutamate, and Glutamine
• Reentry into pathways from which carbon skeletons arose by reverse transamination
Alanine pyruvateAspartate oxaloacetateGlutamate -ketoglutarate
• Glutamine and asparagine are first hydrolyzed to glutamate and aspartate
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B. Arginine, Histidine, and Proline
Fig. 17.27
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C. Glycine and Serine
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D. Threonine
• Alternate routes for the degradation of threonine to glycine
• Figure 17.29 (next slide)
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Fig 17.29 Alternate routes for the degradation of threonine
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E. The Branched-Chain Amino Acids
• Leucine, valine and isoleucine are degraded by related pathways
• The same three enzymes catalyze the first three steps in all pathways
• A branched-chain amino acid transaminase catalyzes the first step
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Fig 17.30 Catabolism of branched-chain amino acids
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F. Methionine
Fig 17.31
(X represents any of a number of methyl-group acceptors)
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F. Methionine
Fig 17.31
(X represents any of a number of methyl-group acceptors)
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Fig 17.31 (cont)
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Fig 17.31 (cont)
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G. Cysteine
Fig 17.32 Conversion of cysteine to pyruvate
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H. Phenylalanine, Tryptophan, and Tyrosine
Fig 17.33
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Fig 17.34 Conversion of tryptophan to alanine and acetyl CoA
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I. Lysine
Fig 17.35
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I. Lysine
Fig 17.35
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Fig 17.35 (cont)
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17.7 The Urea Cycle Converts Ammonia into Urea
• Waste nitrogen must be removed (ammonia is toxic to plants and animals)
• Terrestrial vertebrates synthesize urea (excreted by the kidneys)
• Birds, reptiles synthesize uric acid
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Fig 17.37• Synthesis of carbamoyl
phosphate (removal of NH3)
• Catalyzed by carbamoyl phosphate synthetase I (CPS I)
A. Synthesis of Carbamoyl Phosphate
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Fig 17.37 Synthesis of carbamoyl phosphate (removal of NH3) catalyzed by carbamoyl phosphate synthetase I (CPS I)
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Fig 17.37 (cont)
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B. The Reactions of the Urea Cycle
• Urea cycle (Fig 17.38 & 39 next four slides) Rxn 1 (mitochondria), Rxns 2,3,4 (cytosol)
• Two transport proteins are required: Citrulline-ornithine exchangerGlutamate-aspartate exchanger
• Overall reaction for urea synthesis is:
NH3 + HCO3- + Aspartate + 3 ADP
Urea + Fumarate + 2 ADP + 2 Pi + AMP + PPi
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The Urea Cycle
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C. Ancillary Reactions of the Urea Cycle
• Supply of nitrogen for the urea cycle can be balanced by supply of NH3 and amino acids
• Glutamate dehydrogenase and aspartate transaminase catalyze near equilibrium reactions
• Flux through these enzymes depends upon relative amounts of ammonia and amino acids
• Two cases (next slides): (a) NH3 in excess, (b) aspartate in excess
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Fig 17.40 Balancing the supply of nitrogen for the urea cycle
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NH3 in extreme excess
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Aspartate in extreme excess
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Glucose-alanine cycle
• Some amino acids are deaminated in muscle
• Exchange of glucose and alanine between muscle and liver
• Provides an indirect means for muscle to eliminate nitrogen and replenish its energy supply
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Fig 17.41 Glucose-alanine cycle
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17.8 Renal Glutamine Metabolism Produces Bicarbonate
• Bicarbonate can be lost by buffering H+ in blood
• Bicarbonate can be replenished by glutamine catabolism in the kidneys
• -Ketoglutarate (formed from glutamine oxidation) can be further metabolized to yield bicarbonate
Glutamine -ketoglutarate2- + 2 NH4+
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Glutamine → → -ketoglutarate2- + 2 NH4
+
2 -ketoglutarate2- → → glucose + 4 HCO3-
2C5H10N2O3 + 3O2 + 6H2O → C6H12O6 + 4HCO3-
+ 4NH4+
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Fig 17.42 Loss of bicarbonate as a buffer
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