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Section 8. Amino Acid Metabolism OverviewOverview 11/15/05.

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1 Section 8. Amino Acid Metabolism OverviewOverview 11/15/05

2 Nitrogen Fixation Source of nitrogen for life processes. ~2 x kg/year.Source of nitrogen for life processes. ~2 x kg/year. Rhizobium, other root nodule bacteria, and blue green algae.Rhizobium, other root nodule bacteria, and blue green algae. Nitrogenase complex:Nitrogenase complex: –reductase is a dimer with two 4Fe 4S clusters –nitrogenase is an  2  2 tetramer with two P clusters (Fe, S) and two FeMo cofactors. Source of nitrogen for life processes. ~2 x kg/year.Source of nitrogen for life processes. ~2 x kg/year. Rhizobium, other root nodule bacteria, and blue green algae.Rhizobium, other root nodule bacteria, and blue green algae. Nitrogenase complex:Nitrogenase complex: –reductase is a dimer with two 4Fe 4S clusters –nitrogenase is an  2  2 tetramer with two P clusters (Fe, S) and two FeMo cofactors. Fig

3 Nitrogenase Complex Reactions FeMo cofactor reaction:FeMo cofactor reaction: –N 2  2 NH 3 –N 2 triple bond is 225 kcal/mole. –Notice that H 2 is made also. Reductase reaction:Reductase reaction: –provides 8 e - –16 ATP  16 ADP + 16 Pi. Ferredoxin supplies e - to reductase.Ferredoxin supplies e - to reductase. –8 ferredoxin(red)  8 ferredoxin(ox) + 8 e -. –Ferredoxin(ox) is reduced by photosynthetic centers. FeMo cofactor reaction:FeMo cofactor reaction: –N 2  2 NH 3 –N 2 triple bond is 225 kcal/mole. –Notice that H 2 is made also. Reductase reaction:Reductase reaction: –provides 8 e - –16 ATP  16 ADP + 16 Pi. Ferredoxin supplies e - to reductase.Ferredoxin supplies e - to reductase. –8 ferredoxin(red)  8 ferredoxin(ox) + 8 e -. –Ferredoxin(ox) is reduced by photosynthetic centers. Stryer 4th 2

4 Nitrogen Incorporation into Amino Acids Glutamate dehydrogenase catalyzes NH 4 + addition to  -ketoglutarate to form a protonated Schiff’s base, which is reduced to glutamate.Glutamate dehydrogenase catalyzes NH 4 + addition to  -ketoglutarate to form a protonated Schiff’s base, which is reduced to glutamate. Coupled to oxidation of NADPH (or NADH). Requires cofactor pyridoxal phosphate.Coupled to oxidation of NADPH (or NADH). Requires cofactor pyridoxal phosphate. Glutamine synthetase incorporates a second NH 4 + to make glutamine (see below).Glutamine synthetase incorporates a second NH 4 + to make glutamine (see below). Incorporated nitrogens transferred to make other amino acids.Incorporated nitrogens transferred to make other amino acids. Glutamate dehydrogenase catalyzes NH 4 + addition to  -ketoglutarate to form a protonated Schiff’s base, which is reduced to glutamate.Glutamate dehydrogenase catalyzes NH 4 + addition to  -ketoglutarate to form a protonated Schiff’s base, which is reduced to glutamate. Coupled to oxidation of NADPH (or NADH). Requires cofactor pyridoxal phosphate.Coupled to oxidation of NADPH (or NADH). Requires cofactor pyridoxal phosphate. Glutamine synthetase incorporates a second NH 4 + to make glutamine (see below).Glutamine synthetase incorporates a second NH 4 + to make glutamine (see below). Incorporated nitrogens transferred to make other amino acids.Incorporated nitrogens transferred to make other amino acids. (p. 669) 3

5 Amino Acid Metabolism in Humans 4

6 Nitrogen Excretion in Humans Urea 90%Urea 90% Ammonium 4%Ammonium 4% Creatinine 3%Creatinine 3% Amino acids 1.4%Amino acids 1.4% Uric acid 1%Uric acid 1% Other 0.6%Other 0.6% Urea 90%Urea 90% Ammonium 4%Ammonium 4% Creatinine 3%Creatinine 3% Amino acids 1.4%Amino acids 1.4% Uric acid 1%Uric acid 1% Other 0.6%Other 0.6% 5

7 Examples of Non-protein Nitrogenous Compounds hemeheme pyrimidinespyrimidines purinespurines choline (serine)choline (serine) creatinecreatine bile salts (glycine)bile salts (glycine) Melanin (tyrosine)Melanin (tyrosine) porphyrinsporphyrins epinephrine (phenylalanine)epinephrine (phenylalanine) nicotinic acid (tryptophan)nicotinic acid (tryptophan) hemeheme pyrimidinespyrimidines purinespurines choline (serine)choline (serine) creatinecreatine bile salts (glycine)bile salts (glycine) Melanin (tyrosine)Melanin (tyrosine) porphyrinsporphyrins epinephrine (phenylalanine)epinephrine (phenylalanine) nicotinic acid (tryptophan)nicotinic acid (tryptophan) Almost all nitrogen in human metabolism comes from dietary amino acids.Almost all nitrogen in human metabolism comes from dietary amino acids. To the left are some examples of nitrogen-containing compounds that are made from amino acids.To the left are some examples of nitrogen-containing compounds that are made from amino acids. 6

8 Essential and Nonessential Amino Acids EssentialNonessential histidine alanine proline isoleucine arginineserine leucine asparaginetyrosine lysine aspartate methionine cysteine phenylalanineglutamate threonineglutamine tryptophanglycine valine EssentialNonessential histidine alanine proline isoleucine arginineserine leucine asparaginetyrosine lysine aspartate methionine cysteine phenylalanineglutamate threonineglutamine tryptophanglycine valine 7

9 Biosynthetic Family Schemes These schemes, for bacteria and plants, show biosynthetic families of amino acids made from major metabolic precursors (blue) and from other amino acids (yellow).These schemes, for bacteria and plants, show biosynthetic families of amino acids made from major metabolic precursors (blue) and from other amino acids (yellow). The amino acids in bold are essential for humans.The amino acids in bold are essential for humans. These schemes, for bacteria and plants, show biosynthetic families of amino acids made from major metabolic precursors (blue) and from other amino acids (yellow).These schemes, for bacteria and plants, show biosynthetic families of amino acids made from major metabolic precursors (blue) and from other amino acids (yellow). The amino acids in bold are essential for humans.The amino acids in bold are essential for humans. 8

10 Amino Acids and  -Keto Acids Every amino acid has a corresponding  - keto acid (carbon skeleton).Every amino acid has a corresponding  - keto acid (carbon skeleton). Each amino acid and its keto acid are interconvertible by transaminiation reactions.Each amino acid and its keto acid are interconvertible by transaminiation reactions. It is our inability to synthesize the carbon skeletons that makes certain amino acids essential to the human diet.It is our inability to synthesize the carbon skeletons that makes certain amino acids essential to the human diet. Every amino acid has a corresponding  - keto acid (carbon skeleton).Every amino acid has a corresponding  - keto acid (carbon skeleton). Each amino acid and its keto acid are interconvertible by transaminiation reactions.Each amino acid and its keto acid are interconvertible by transaminiation reactions. It is our inability to synthesize the carbon skeletons that makes certain amino acids essential to the human diet.It is our inability to synthesize the carbon skeletons that makes certain amino acids essential to the human diet. 9

11 Vitamin B 6 and Pyridoxal Phosphate The vitamin form, an alcohol, is oxidized to the aldehyde level.The vitamin form, an alcohol, is oxidized to the aldehyde level. The coenzyme is pyridoxal phosphate.The coenzyme is pyridoxal phosphate. During transaminiation reactions, the pyridoxal group is transiently converted to pyridoxamine.During transaminiation reactions, the pyridoxal group is transiently converted to pyridoxamine. The vitamin form, an alcohol, is oxidized to the aldehyde level.The vitamin form, an alcohol, is oxidized to the aldehyde level. The coenzyme is pyridoxal phosphate.The coenzyme is pyridoxal phosphate. During transaminiation reactions, the pyridoxal group is transiently converted to pyridoxamine.During transaminiation reactions, the pyridoxal group is transiently converted to pyridoxamine. 10

12 Catalytic Intermediate A Schiff base is formed by pyridoxal phosphate and an amino acid.A Schiff base is formed by pyridoxal phosphate and an amino acid. All the bonds to the  -carbon on the amino acid are weaker and more labile.All the bonds to the  -carbon on the amino acid are weaker and more labile. –a: aminotransferase –b: decarboxylase –c: aldolase N + of lower structure contributes to weakening the a, b and c bonds.N + of lower structure contributes to weakening the a, b and c bonds. A Schiff base is formed by pyridoxal phosphate and an amino acid.A Schiff base is formed by pyridoxal phosphate and an amino acid. All the bonds to the  -carbon on the amino acid are weaker and more labile.All the bonds to the  -carbon on the amino acid are weaker and more labile. –a: aminotransferase –b: decarboxylase –c: aldolase N + of lower structure contributes to weakening the a, b and c bonds.N + of lower structure contributes to weakening the a, b and c bonds. 11

13 Reactions in an Aminotransferase Active Site Dehydration attaches an amino acid to enzyme- bound PLP, forming a Schiff base.Dehydration attaches an amino acid to enzyme- bound PLP, forming a Schiff base. The aldimine is converted to ketimine.The aldimine is converted to ketimine. Hydrolysis frees the  - keto acid.Hydrolysis frees the  - keto acid. Dehydration attaches an amino acid to enzyme- bound PLP, forming a Schiff base.Dehydration attaches an amino acid to enzyme- bound PLP, forming a Schiff base. The aldimine is converted to ketimine.The aldimine is converted to ketimine. Hydrolysis frees the  - keto acid.Hydrolysis frees the  - keto acid. 12

14 Transamination Mechanism Upper Left side: Amino acid 1 binds and is converted to a keto acid.Upper Left side: Amino acid 1 binds and is converted to a keto acid. Lower right side: Keto acid 2 binds and is converted to an amino acid.Lower right side: Keto acid 2 binds and is converted to an amino acid. Upper Left side: Amino acid 1 binds and is converted to a keto acid.Upper Left side: Amino acid 1 binds and is converted to a keto acid. Lower right side: Keto acid 2 binds and is converted to an amino acid.Lower right side: Keto acid 2 binds and is converted to an amino acid. 13

15 Catabolism of Amino Acids Amino acids provide about 15% of human metabolic energy.Amino acids provide about 15% of human metabolic energy. Peripheral tissues are the primary sites of amino acid catabolism, converting the carbon skeletons into pyruvate, acetyl CoA, acetoacetyl CoA,  -ketoglutarate, succinyl CoA, fumarate or oxaloacetate.Peripheral tissues are the primary sites of amino acid catabolism, converting the carbon skeletons into pyruvate, acetyl CoA, acetoacetyl CoA,  -ketoglutarate, succinyl CoA, fumarate or oxaloacetate. Amino groups are removed, converted to urea and excreted.Amino groups are removed, converted to urea and excreted. When necessary, peripheral tissue amino groups can be transported to the liver as part of alanine (or glutamine).When necessary, peripheral tissue amino groups can be transported to the liver as part of alanine (or glutamine). In the liver, alanine is converted back into pyruvate (suitable for gluconeogenesis), and the amino group is transferred to glutamate and then to the urea cycle.In the liver, alanine is converted back into pyruvate (suitable for gluconeogenesis), and the amino group is transferred to glutamate and then to the urea cycle. Amino acids provide about 15% of human metabolic energy.Amino acids provide about 15% of human metabolic energy. Peripheral tissues are the primary sites of amino acid catabolism, converting the carbon skeletons into pyruvate, acetyl CoA, acetoacetyl CoA,  -ketoglutarate, succinyl CoA, fumarate or oxaloacetate.Peripheral tissues are the primary sites of amino acid catabolism, converting the carbon skeletons into pyruvate, acetyl CoA, acetoacetyl CoA,  -ketoglutarate, succinyl CoA, fumarate or oxaloacetate. Amino groups are removed, converted to urea and excreted.Amino groups are removed, converted to urea and excreted. When necessary, peripheral tissue amino groups can be transported to the liver as part of alanine (or glutamine).When necessary, peripheral tissue amino groups can be transported to the liver as part of alanine (or glutamine). In the liver, alanine is converted back into pyruvate (suitable for gluconeogenesis), and the amino group is transferred to glutamate and then to the urea cycle.In the liver, alanine is converted back into pyruvate (suitable for gluconeogenesis), and the amino group is transferred to glutamate and then to the urea cycle. 14 Peripheral tissueLiver

16 Common Amino Group Carriers Alanine aminotransferase and glutamate aminotransferase are the catalysts.Alanine aminotransferase and glutamate aminotransferase are the catalysts. 15

17 Clinical Measures of Tissue Damage Alanine aminotransferase (ALT), also known as serum glutamic pyruvic transaminase (SGPT) is normally more concentrated in the liver, compared to other locatons. It is released into the bloodstream as the result of liver injury and serves as a fairly specific indicator of liver status. Aspartate aminotransferase (AST), also known as serum glutamic oxaloacetic transaminase (SGOT) is, by contrast, normally found in a diversity of tissues including liver, heart, muscle, kidney, and brain. It is released into serum when any one of these tissues is damaged. For example, its level in serum rises with heart attacks and with muscle disorders. Alanine aminotransferase (ALT), also known as serum glutamic pyruvic transaminase (SGPT) is normally more concentrated in the liver, compared to other locatons. It is released into the bloodstream as the result of liver injury and serves as a fairly specific indicator of liver status. Aspartate aminotransferase (AST), also known as serum glutamic oxaloacetic transaminase (SGOT) is, by contrast, normally found in a diversity of tissues including liver, heart, muscle, kidney, and brain. It is released into serum when any one of these tissues is damaged. For example, its level in serum rises with heart attacks and with muscle disorders. 16

18 Web links Nitrogen FixationNitrogen Fixation. A summary of the topic. Nitrogen Fixation Nitrogen CycleNitrogen Cycle. The biological big picture. Nitrogen Cycle Amino Acid MetabolismAmino Acid Metabolism. Reviews reactions. Amino Acid Metabolism Next topic: Urea cycle Web links Nitrogen FixationNitrogen Fixation. A summary of the topic. Nitrogen Fixation Nitrogen CycleNitrogen Cycle. The biological big picture. Nitrogen Cycle Amino Acid MetabolismAmino Acid Metabolism. Reviews reactions. Amino Acid Metabolism Next topic: Urea cycle


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