Biochemistry 304 2014 Student Edition Amino Acid Metabolism

download report

Transcript Biochemistry 304 2014 Student Edition Amino Acid Metabolism

Amino Acid Metabolism

Student Edition

6/3/13 version

Dr. Brad Chazotte 213 Maddox Hall [email protected]

Web Site: http://www.campbell.edu/faculty/chazotte

Pharm. 304 Biochemistry

Original material only ©2004-14 B. Chazotte

Fall 2014

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.

Nitrogen Pathways in Intermediary Metabolism Plants

Matthews et al 2000 Figure 20.1

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

Protein Synthesis & Degradation

1.

2.

3.

Nutrient storage as protein; break proteins down in times of metabolic need (muscle a prime source) Eliminate accumulation of abnormal proteins that would harm the cell Permit the regulation of cellular metabolism by the elimination of unneeded enzymes and regulatory proteins.

Voet, Voet & Pratt 2008 p.733

Catabolism

Cellular Protein Degradative Routes

Lysosomal a cellular compartment at ~pH 5 containing hydrolytic enzymes (cathepsins). Degrade substances taken up by endocytosis. Recycle intra cellular constituents enclosed within vacuoles. In “well nourished cells” protein degradation is non selective. 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.

R x Involved in Protein Ubiquination

Proteasome Matthews et al 2000 Figure 20.10

Voet, Voet & Pratt 2013 Fig 21.2

Matthews et al 2000 Figure 20.11

Voet, Voet & Pratt 2013 Fig 21.4

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

Some Cellular Processes Regulated by Protein Degradation

e.g,NF-κB –I κB system Berg, Tymoczko, & Stryer 2012 Table 23.3

Protein (“Macro”) Digestion in the Human Gastrointestinal Tract

Berg, Tymoczko, & Stryer 2012 Figure 23.1

Lehninger 2000 Figure 18.3

Amino Acid Catabolism: Overview

Amino acid degradation includes a key step of separating the amino group from the carbon skeleton.

Lehninger 2004 Figure 18.1

Voet, Voet & Pratt 2013 Fig 21.6

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 Voet, Voet & Pratt 2013 Chap. 21 page 719

Oxidative Deamination

– of glutamate by glutamate dehydrogenase yields ammonia and  -ketoglutarate Voet, Voet & Pratt 2013 Chap. 21 page 722

Forms of Pyridoxal-5’ Phosphate

Needed by aminotransferases as a coenzyme.

Voet, Voet & Pratt 2013

Fig 21.7

PLP-Dependent Enzyme Catalyzed Transamination Mechanism

Voet, Voet & Pratt 2013 Fig 21.8

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

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.

mammalian liver Lehninger 2000 Figure 18.7

Ammonia Transport to Liver for Urea Synthesis

Matthews et al 2000 Figure 20.14

Lehninger 2000 Figure 18.8

Urea Cycle

Urea Cycle Enzymes

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

Overall Urea Cycle Reaction

Voet, Voet & Pratt 2013

Chap 21 p 723

Urea Cycle & Feeder Reactions

Voet, Voet & Pratt 2013 Fig 21.9

Lehninger 2000 Figure 18.9

Urea Cycle Diagram

Lehninger 2000 Figure 18.9

Nitrogen-acquiring reactions in Urea Synthesis

Lehninger 2004 Figure 18.11

Linking the Urea & Citric Acid Cycles “ Krebs ‘Bicycle’ ”

Lehninger 2004 Figure 18.12

AA Degradation to 1 of 7 Common Intermediates

Voet, Voet & Pratt 2013 Fig 21.13

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

Examples of a Few Disorders of Human Amino Acid Catabolism

PKU Tyrosimenia I, II, or III R x 5, 2, or 4- respectively {side 35} Lehninger 2000 Table 18.2

Anabolism

Human Essential & Non-Essential Amino Acid

Voet, Voet & Pratt 2013

Table 21.3

Amino Acid Biosynthetic Families CAC Glycolysis Glycolysis CAC PP

PP Lehninger 2000 Table 22.1

Metabolic Relationships Among Amino Acids Derived from Citric Acid Cycle Intermediates

Essential Human amino acid

THOSE AA HIGHLIGTED BY AN ORANGE BOX ARE ESSENTIAL AMINO ACIDS FOR HUMANS.

Matthews et al 2000 Figure 21.1

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.

End of Lecture Materials

Supplementary Material on Amino Acid Catabolism • This material will

NOT

be on any test and is for informational purposes only.

Pathways for Ala, Cys, Gly, Ser & Thr to Pyruvate

Voet, Voet & Pratt 2008

Fig 21.14

Serine Dehydratase

Voet, Voet & Pratt 2008 Fig 21.15

Pathways for Arginine, Glutamate, Glutamine, Histidine & Proline to

ketoglutarate

Voet, Voet & Pratt 2008 Fig 21.17

Methionine Degradation

Voet, Voet & Pratt 2008 Fig 21.18

TetraHydroFolate 2-State Reduction of Folate to THF

Voet, Voet & Pratt 2008

Table 21.2, Fig 21.19

Branched-Chain AA Degradation

Voet, Voet & Pratt 2008

Fig 21.21

Mammalian Liver Lysine Degradation

Enoyl-CoA dehydratase Saccharopine dehydrogenase Saccharopine dehydrogenase aminoadipate semialdehyde dehydrogenase Sminoadipate amino transferase Α-keto acid dehydrogenase Glutaryl-CoA dehyd.

decarboxylase Β-hydrozyacylCoA dehydrogenase HMG-CoA synthase HMG-CoA lyase

1

Voet, Voet & Pratt 2008 Fig 21.22

Tryptophan Degradation

formamidase Tryptophan-2,3 dioxygenase Kynureninase-3 monooxygenase Kynureninase

Voet, Voet & Pratt 2008

Fig 21.23

Phenylalanine Degradation

Phenylalanine hydroxylase Tyrosine aminotransferase p-hydroxyphenyl pyruvate dioxygenase Homogentisate dioxygenase fumarylacetoacetase

Voet, Voet & Pratt 2008

Fig 21.24

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.

Alanine, Aspartate, Glutamate, Asparagine & Glutamine Syntheses (Non-essential)

Voet, Voet & Pratt 2008

Fig 21.27

Glutamate “Family” Syntheses: Arginine, Ornithine & Proline

Pyrroline carboxylate reductase γ-glutamyl kinase Glutamate dehydrogenase Path in mammals Voet, Voet & Pratt 2008 Fig 21.30

3-Phosphoglycerate

Serine Conversion

3-phosphoglycerate dehydrogenase Phosphoserine aminotransferase Phosphoserine phosphotase Voet, Voet & Pratt 2008

Figure 21.31

Biosynthesis of Essential Amino Acids

Biosyntheses of Aspartate “Family”: Lysine, Methionine, & Threonine

Voet, Voet & Pratt 2008 Fig 21.32

Biosyntheses of the Pyruvate “Family”: Isoleucine, leucine & Valine

Voet, Voet & Pratt 2008

Figure 21.33

Biosyntheses of Phenylalanine, Tryptophan, & Tyrosine

Voet, Voet & Pratt 2008 Fig 21.34

Biosynthesis of Histidine

Voet, Voet & Pratt 2008 Fig 21.36

Heme Biosynthesis

Voet, Voet & Pratt 2008 Fig 21.38

Summary: Glucogenic & Ketogenic Amino Acids

Lehninger 2000 Figure 18.29

Amino Acid Biosynthesis: Overview I

Lehninger 2000 Figure 22.9a

Amino Acid Biosynthesis: Overview II

Lehninger 2000 Figure 22.9b

Amino Acid Biosynthesis: Overview III

Lehninger 2000 Figure 22.9c

End of Supplementary Material