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Amino Acid Metabolism Student Edition 6/3/13 version Pharm. 304 Biochemistry Fall 2014 Dr. Brad Chazotte 213 Maddox Hall Web Site:

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Presentation on theme: "Amino Acid Metabolism Student Edition 6/3/13 version Pharm. 304 Biochemistry Fall 2014 Dr. Brad Chazotte 213 Maddox Hall Web Site:"— Presentation transcript:

1 Amino Acid Metabolism Student Edition 6/3/13 version Pharm. 304 Biochemistry Fall 2014 Dr. Brad Chazotte 213 Maddox Hall Web Site: Original material only © B. Chazotte

2 Goals Understand the relationship of nitrogen to carbon intermediary metabolism. Learn the Urea Cycle sequence, reactions, and products. Have an understanding of an overview of amino acid catabolism resulting in 7 basic products and the difference between ketogenic and glucogenic catabolism. Have an understanding of an overview of amino acid anabolism from basic precursors. Understand the concept of essential and nonessential amino acids in the diet of humans. Understand that many diseases can arise from errors in amino acid metabolism. Do NOT memorize any of the specific amino acid catabolic or anabolic pathways. They are for informational purposes only.

3 Nitrogen Pathways in Intermediary Metabolism Matthews et al 2000 Figure 20.1 Plants

4 Dietary Amino Acids in Metabolism “Excess dietary amino acids are not simply excreted but are converted to common metabolites that are precursors of glucose, fatty acids, ketone bodies – and are therefore metabolic fuels” Voet, Voet & Pratt 2008 p.732

5 Protein Synthesis & Degradation 1.Nutrient storage as protein; break proteins down in times of metabolic need (muscle a prime source) 2.Eliminate accumulation of abnormal proteins that would harm the cell 3.Permit the regulation of cellular metabolism by the elimination of unneeded enzymes and regulatory proteins. Voet, Voet & Pratt 2008 p.733

6 Catabolism

7 Cellular Protein Degradative Routes Lysosomal - a cellular compartment at ~pH 5 containing hydrolytic enzymes (cathepsins). Degrade substances taken up by endocytosis. Recycle intracellular constituents enclosed within vacuoles. In “well nourished cells” protein degradation is nonselective. In starving cells a selective pathway is activated that imports and degrades proteins that contain the pentapeptide (Lys-Phe-Glu-Arg-Gln; KFERQ) e.g., in muscle and liver, but not brain. Ubiquitin-Based – ATP-based process independent of lysosomes. Proteins are marked for degradation by linking to ubiquitin.

8 R x Involved in Protein Ubiquination Voet, Voet & Pratt 2013 Fig 21.2Matthews et al 2000 Figure Matthews et al 2000 Figure Proteasome Voet, Voet & Pratt 2013 Fig 21.4

9 Distinguishing Protein Lifetimes The N-end Rule: N-terminal residues Asp, Arg, Leu, Lys & Phe half-life ~ 2-3 minutes Ala, Gly, Met, Ser Thr, & Val half-life > 20 hrs in eukaryotes (>10 prokaryotes) PEST proteins Proteins with segments rich in Pro, Glu, Ser, & Thr are rapidily degraded- these AA have sites that can be phosphorylated – thus targeting them for ubiquitination. Voet, Voet & Pratt 2013 Table 21.1

10 Some Cellular Processes Regulated by Protein Degradation e.g,NF-κB –I κB system Berg, Tymoczko, & Stryer 2012 Table 23.3

11 Protein (“Macro”) Digestion in the Human Gastrointestinal Tract Lehninger 2000 Figure 18.3 Berg, Tymoczko, & Stryer 2012 Figure 23.1

12 Amino Acid Catabolism: Overview Voet, Voet & Pratt 2013 Fig 21.6 Lehninger 2004 Figure 18.1 Amino acid degradation includes a key step of separating the amino group from the carbon skeleton.

13 Amino Acid Deamination Transamination - most amino acids are deaminated by this process carried out by transaminases (aminotransferases). Amino group of amino acid is transferred (predominately) to  -ketoglutarate Oxidative Deamination – of glutamate by glutamate dehydrogenase yields ammonia and  -ketoglutarate Voet, Voet & Pratt 2013 Chap. 21 page 722 Voet, Voet & Pratt 2013 Chap. 21 page 719

14 Forms of Pyridoxal-5’- Phosphate Voet, Voet & Pratt 2013 Fig 21.7 Needed by aminotransferases as a coenzyme.

15 PLP-Dependent Enzyme Catalyzed Transamination Mechanism Voet, Voet & Pratt 2013 Fig 21.8

16 Oxidative Degradation of Amino Acids Occurs under three different circumstances in animals: 1)During normal homeostasis 2) Protein-rich diet 3)Starvation or uncontrolled diabetes mellitus Lehninger 2000 Chapter 18

17 Glutamate Dehydrogenase (Oxidative Deamination) A mitochondrial enzyme yielding ammonia and  -ketoglutarate It is the only enzyme that can accept either NAD + or NADP + as a coenzyme  G° = ~30 kJ mol -1 Due to the high toxicity of ammonia – it is important that under physiological conditions  G ≈ 0, i.e. at equilibrium. Lehninger 2000 Figure 18.7 mammalian liver

18 Ammonia Transport to Liver for Urea Synthesis Matthews et al 2000 Figure 20.14Lehninger 2000 Figure 18.8

19 Urea Cycle

20 Urea Cycle Enzymes (1)Carbamoyl Phosphate synthetase (mitochondrion) (2)Ornithine transcarbamoylase (mitochondrion) (3)Argininosuccinate synthetase (cell cytosol) (4)Argininosuccinase (cell cytosol) (5)Arginase (cell cytosol)

21 Overall Urea Cycle Reaction Voet, Voet & Pratt 2013 Chap 21 p 723

22 Urea Cycle & Feeder Reactions Voet, Voet & Pratt 2013 Fig 21.9 Lehninger 2000 Figure 18.9

23 Urea Cycle Diagram Lehninger 2000 Figure 18.9

24 Nitrogen-acquiring reactions in Urea Synthesis Lehninger 2004 Figure 18.11

25 Linking the Urea & Citric Acid Cycles “ Krebs ‘Bicycle’ ” Lehninger 2004 Figure 18.12

26 AA Degradation to 1 of 7 Common Intermediates Voet, Voet & Pratt 2013 Fig 21.13

27 Glucogenic vs Ketogenic Amino Acid Degradation Glucogenic - degradation lead to glucose precusors: pyruvate, α-ketoglutarate, succinyl-CoA, fumarate or oxaloacetate Ketogenic – degradation leads to fatty acids or ketone body precursors: acetyl-CoA or acetoacetate Some amino acids are gluco- and keto-genic

28 Examples of a Few Disorders of Human Amino Acid Catabolism Lehninger 2000 Table 18.2 PKU Tyrosimenia I, II, or IIIR x 5, 2, or 4- respectively {side 35}

29 Anabolism

30 Human Essential & Non-Essential Amino Acid Voet, Voet & Pratt 2013 Table 21.3

31 Amino Acid Biosynthetic Families Lehninger 2000 Table 22.1 CAC Glycolysis PP

32 Metabolic Relationships Among Amino Acids Derived from Citric Acid Cycle Intermediates Matthews et al 2000 Figure 21.1 Essential Human amino acid THOSE AA HIGHLIGTED BY AN ORANGE BOX ARE ESSENTIAL AMINO ACIDS FOR HUMANS.

33 Biosynthesis of Non-Essential Amino Acids With the exception of tyrosine, all the nonessential amino acids come from one these four metabolic intermediates: pyruvate, oxaloacetate, α-ketoglutarate, and 3-phosphoglycerate.

34 End of Lecture Materials

35 Supplementary Material on Amino Acid Catabolism This material will NOT be on any test and is for informational purposes only.

36 Pathways for Ala, Cys, Gly, Ser & Thr to Pyruvate Voet, Voet & Pratt 2008 Fig 21.14

37 Serine Dehydratase Voet, Voet & Pratt 2008 Fig 21.15

38 Pathways for Arginine, Glutamate, Glutamine, Histidine & Proline to  - ketoglutarate Voet, Voet & Pratt 2008 Fig 21.17

39 Methionine Degradation Voet, Voet & Pratt 2008 Fig 21.18

40 TetraHydroFolate Voet, Voet & Pratt 2008 Table 21.2, Fig State Reduction of Folate to THF

41 Branched-Chain AA Degradation Voet, Voet & Pratt 2008 Fig 21.21

42 Mammalian Liver Lysine Degradation Voet, Voet & Pratt 2008 Fig Saccharopine dehydrogenase aminoadipate semialdehyde dehydrogenase Sminoadipate amino- transferase Α-keto acid dehydrogenase Glutaryl-CoA dehyd. decarboxylase Enoyl-CoA dehydratase Β-hydrozyacylCoA dehydrogenase HMG-CoA synthase HMG-CoA lyase 1

43 Tryptophan Degradation Voet, Voet & Pratt 2008 Fig Tryptophan-2,3- dioxygenase formamidase Kynureninase-3- monooxygenase Kynureninase

44 Phenylalanine Degradation Voet, Voet & Pratt 2008 Fig Phenylalanine hydroxylase Tyrosine aminotransferase p-hydroxyphenyl pyruvate dioxygenase Homogentisate dioxygenase fumarylacetoacetase

45 Supplementary Information of Amino Acid Anabolism The information in the slides hereafter is for informational purposes only, if you are interested, and will NOT be part of any test. Amino acid degradative and biosynthetic pathways are sites for a significant number of illnesses and/or genetic defects.

46 Alanine, Aspartate, Glutamate, Asparagine & Glutamine Syntheses (Non-essential) Voet, Voet & Pratt 2008 Fig 21.27

47 Glutamate “Family” Syntheses: Arginine, Ornithine & Proline Voet, Voet & Pratt 2008 Fig γ-glutamyl kinase Glutamate dehydrogenase Pyrroline carboxylate reductase Path in mammals

48 3-Phosphoglycerate  Serine Conversion Voet, Voet & Pratt 2008 Figure phosphoglycerate dehydrogenase Phosphoserine aminotransferase Phosphoserine phosphotase

49 Biosynthesis of Essential Amino Acids

50 Biosyntheses of Aspartate “Family”: Lysine, Methionine, & Threonine Voet, Voet & Pratt 2008 Fig 21.32

51 Biosyntheses of the Pyruvate “Family”: Isoleucine, leucine & Valine Voet, Voet & Pratt 2008 Figure 21.33

52 Biosyntheses of Phenylalanine, Tryptophan, & Tyrosine Voet, Voet & Pratt 2008 Fig 21.34

53 Biosynthesis of Histidine Voet, Voet & Pratt 2008 Fig 21.36

54 Heme Biosynthesis Voet, Voet & Pratt 2008 Fig 21.38

55 Summary: Glucogenic & Ketogenic Amino Acids Lehninger 2000 Figure 18.29

56 Amino Acid Biosynthesis: Overview I Lehninger 2000 Figure 22.9a

57 Amino Acid Biosynthesis: Overview II Lehninger 2000 Figure 22.9b

58 Amino Acid Biosynthesis: Overview III Lehninger 2000 Figure 22.9c

59 End of Supplementary Material


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