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Amino acid metabolism, concluded Andy Howard Introductory Biochemistry 24 April 2008 What we’ll cover Amino acid metabolism Non-essential amino acids Branched-chain Aromatics Histidine Amino acids as metabolites Amino Acid metabolism Glucogenic amino acids Ketogenic amino acids Serine biproducts Glycine biproducts p. 2 of 44 24 April 2008 Essential and non-essential amino acids An amino acid is defined as essential if it must be obtained within the diet In general the essential amino acids are the ones that have complicated and highly ATP-dependent biosynthetic pathways Of course, it depends on the organism Amino Acid metabolism p. 3 of 44 24 April 2008 The human list (cf. box 17.3) AA moles ATP Asp Asn Lys Met Thr Ala Val Leu Ile 21 22-24 50-51 44 31 20 39 47 55 Glu Gln 30 31 essential? no no yes yes yes no yes yes yes no no Amino Acid metabolism AA moles ATP Arg Pro Ser Gly Cys Phe Tyr Trp His 44 39 18 12 19 65 62 78 42 p. 4 of 44 essential? no no no no no yes no* yes yes 24 April 2008 Examples of transaminases Reactants Products Keto acid amino acid Pyruvate glutamate Pyruvate aspartate Oxaloacetate glutamate 3-P-OH-pyr glutamate 3-OH-phenyl- glutamate pyruvate Glu-g(glu) semialdehyde N-acylglutamate 2-amino6-oxopimelate keto acid -k-glutarate oxaloacetate -k-glutarate -k-glutarate -k-glutarate amino acid alanine pyruvate alanine pyruvate aspartate aspartate P-ser phosphoserine tyrosine tyrosine (-k-g) ornithine ornithine Amino Acid metabolism Transaminase -k-glutarate N-acyl- 2.3.1.89 2-6,diaminopimelate p. 5 of 44 24 April 2008 Marching through the list of twenty amino acids Amino acids we’ve already covered Acids and amides: glu, gln, asp, asn Simple: ala, ser, gly New but nonessential arg, pro cys Amino Acid metabolism Essential but straightforward lys, met, thr val, leu, ile Essential & Ugly phe, tyr, trp his p. 6 of 44 24 April 2008 Glutamate semialdehyde Arginine and proline Two routes: Glutamate to glutamate semialdehyde that cyclizes to 1-pyrroline 5-carboxylate and thence to proline Glutamate semialdehyde can also be converted to ornithine and thence to arg Alternative: glutamate acetylated to Nacetyl-glutamate-5-semialdehyde and thence to ornithine Amino Acid metabolism p. 7 of 44 ornithine 24 April 2008 Glutamate to P5C Single enzyme can interconvert glutamate and 1-pyrroline carboxylate: 1-pyrroline-5-carboxylate dehydrogenase 3-layer sandwich protein Amino Acid metabolism p. 8 of 44 PDB 2BJA 170 kDa trimer monomer shown Thermus thermophilus 24 April 2008 Pyrroline-5-carboxylate to proline Pyrroline-5carboxylate reduced to proline Large, NAD(P)dependent enzyme Amino Acid metabolism Pyrroline-5-carboxylate reductase PDB 2IZZ 354 kDa decamer pentamer shown Human p. 9 of 44 24 April 2008 Glutamate to Glu semialdehyde Glu-5-P Glu is -phosphorylated: glu + ATP glu-5-P + ADP (2.7.2.11) Glu-5-P is reduced and dephosphorylated: glu-5-P + NADPH + H+ glu-5-semialdehyde + -glutamyl phosphate NADP+ Amino Acid metabolism reductase PDB 1O20 47 kDa monomer Thermatoga maritima p. 10 of 44 24 April 2008 Glu semialdehyde to ornithine ornithine This is just another transamination, catalyzed by ornithine aminotransferase: glu-5-semialdehyde + glu/asp ornithine + -keto-glutarate / oxaloacetate Typical PLPdependent reaction Amino Acid metabolism p. 11 of 44 PDB 2OAT 193 kDa tetramer human 24 April 2008 Ornithine to citrulline Carbamoyl phosphate Ornithine condenses with carbamoyl phosphate to form citrulline with the help of ornithine transcarbamoylase Amino Acid metabolism citrulline PDB 1DUV 110 kDa trimer E.coil p. 12 of 44 24 April 2008 Citrulline to arginosuccinate Citrulline condenses with aspartate using ATP hydrolysis to drive it forward to Larginosuccinate: citrulline + aspartate + ATP L-arginosuccinate + AMP + PPi Amino Acid metabolism p. 13 of 44 Arginosuccinate synthase 200 kDa tetramer monomer shown 24 April 2008 Arginosuccinate to arginine fumarate Fumarate extracted, leaving arginine Arginosuccinate lyase is also -crystallin, one of the moonlighting proteins: it’s a component of eye lenses Amino Acid metabolism p. 14 of 44 PDB 1TJ7 100 kDa dimer (really!) E.coli 24 April 2008 Why all that detail? These reactions form 75% of the urea cycle, which is an important path for amino acid and nucleic acid degradation. So we’ll need this later. Amino Acid metabolism p. 15 of 44 24 April 2008 Cysteine synthesis in plants and bacteria serine + Acetyl CoA O-acetylserine + HSCoA O-acetylserine + S2- + H+ cysteine + acetate Ser acetyltransferase is inhibited by cysteine Serine acetyltransferase PDB 1SSQ 176 kDa hexamer dimer shown Haemophilus O-acetylserine Amino Acid metabolism p. 16 of 44 24 April 2008 Animal pathway to cys cystathionine Ser + homocysteine (from met) fuse to form cystathionine + H2O Cystathionine + H2O NH4+ + Cystathionine -lyase cysteine + PDB 1N8P ketobutyrate 173 kDa tetramer yeast Amino Acid metabolism p. 17 of 44 24 April 2008 Lys, met, thr asp gets phosphorylated and becomes a source for all of these: Asp + ATP -aspartyl phosphate + ADP via aspartate kinase -asp P + NADPH + H+ -> Pi + aspartate -semialdehyde +NADP+ This heads to lys or to homoserine Homoserine converts in a few steps to met or thr Amino Acid metabolism p. 18 of 44 Aspartate kinase 112 kDa PDB 2CDQ dimer Arabidopsis 24 April 2008 Asp -semialdehyde to homoserine -aldehyde reduced to secalcohol, which is homoserine Homo is generally a prefix meaning containing an extra methylene group This is precursor to homocysteine methionine It also leads to threonine Amino Acid metabolism p. 19 of 44 homoserine 24 April 2008 Homoserine to threonine Phosphohomoserine Homoserine phosphorylated with ATP as phosphate donor threonine Phosphohomoserine dephosporylated with movement of -OH from one carbon to another: threonine results Amino Acid metabolism p. 20 of 44 24 April 2008 Homoserine to methionine Three reactions convert homoserine to homocysteine 5-methyltetrahydrofolate serves as a methyl donor to convert homocysteine to methionine via methionine synthase This enzyme exists in humans but its activity is low and [homocysteine] is low; So methionine is essential in humans Amino Acid metabolism p. 21 of 44 homocysteine 24 April 2008 Specifics for lysine 2,3-dihydropicolinate Aspartyl semialdehyde condenses with pyruvate to form 2-3-dihydropicolinate Reduced again to 2,3,4,5-tetrahydropicolinate Acylated (via AcylCoA) to N-acyl-2-amino-6oxopimelate Transaminated to N-acyl-2,6-diaminopimelate Deacylated to L,L-N-acyl-2,6-diaminopimelate Epimerase converts that to meso form That’s decarboxylated to lysine Amino Acid metabolism p. 22 of 44 24 April 2008 The human list (cf. box 17.3) AA moles ATP Asp Asn Lys Met Thr Ala Val Leu Ile 21 22-24 50-51 44 31 20 39 47 55 Glu Gln 30 31 essential? no no yes yes yes no yes yes yes no no Amino Acid metabolism AA moles ATP Arg Pro Ser Gly Cys Phe Tyr Trp His 44 39 18 12 19 65 62 78 42 p. 23 of 44 essential? no no no no no yes no* yes yes 24 April 2008 Branched-chain aliphatics: isoleucine and valine -ketobutyrate Derived from pyruvate or ketobutyrate 2 pyruvate -ketoisovalerate + CO2 pyr + -ketobutyrate -keto--methylvalerate + CO2 These products are transaminated to ile and val Amino Acid metabolism p. 24 of 44 -keto -methylvalerate 24 April 2008 Leucine Also derived from -ketoisovalerate; An extra methylene is inserted between the polar end and the isopropyl group Final reaction is another transamination Amino Acid metabolism p. 25 of 44 24 April 2008 shikimate Aromatics: phe and tyr Common pathways for phe,tyr,trp via shikimate and chorismate For phe, tyr: chorismate converted to prephenate Prephenate can be aromatized with or without a 4-OH group to lead to phe,tyr Amino Acid metabolism p. 26 of 44 chorismate 24 April 2008 Reaction specifics Prephenate is oxidized and dehydroxylated in two steps to phenylpyruvate Or it is oxidized to 4-OHphenylpyruvate Transaminations of those -ketoacids yield the final amino acids Amino Acid metabolism p. 27 of 44 prephenate 4-hydroxyphenylpyruvate 24 April 2008 Chorismate mutase Isomerase, converts chorismate to prephenate In E.coli: 2 versions depending on which path the product is heading to Active sites are similar in all organisms but architecture is very different Catalytic triad similar to serine proteases Amino Acid metabolism p. 28 of 44 PDB 1DBF 42 kDa trimer B.subtilis 24 April 2008 Path to tryptophan: anthranilate synthase anthranilate Chorismate reacts with glutamine and is aromatized to anthranilate: chorismate + gln anthranilate + pyruvate + glutamate Amino Acid metabolism p. 29 of 44 PDB 1I1Q 157 kDa heterotetramer heterodimer shown Salmonella 24 April 2008 Anthranilate to indole Four-step pathway: phosphoribosyl pyrophosphate (PRPP) contributes a phosphoribosyl group Sugar ring opens and rearranges Result is decarboxylated and forms a second ring to form indole 3-glycerinphosphate Glyceraldehyde-3-P is released to leave indole Amino Acid metabolism p. 30 of 44 24 April 2008 Tryptophan synthase Indole + ser tryptophan + H2O PLP-dependent enzyme, but different in how it uses PLP from the transaminases Amino Acid metabolism p. 31 of 44 PDB 2CLF 146 kDa heterotetramer; heterodimer shown Salmonella 24 April 2008 Genetic control of aromatic aa synthesis In E.coli and other bacteria, a single operon controls several chorismaterelated genes Amino Acid metabolism p. 32 of 44 24 April 2008 Histidine (fig. 17.22) Start with PRPP and ATP: form phosphoribosyl ATP 3 reactions involving glutamine as nitrogen donor for ring lead to imidazole glycerol phosphate That gets modified and transaminated t make histidine Amino Acid metabolism p. 33 of 44 24 April 2008 What do we do with amino acids? Obviously a lot of them serve as buildingblocks for protein and peptide synthesis via ribosomal mechanisms Also serve as metabolites, getting converted to other compounds or getting oxidized as fuel Amino Acid metabolism p. 34 of 44 24 April 2008 Gluogenic and ketogenic amino acids Degradation of many amino acids lead to TCA cycle intermediates or pyruvate therefore these can be built back up to glucose; these are called glucogenic Degradation of others leads to acetyl CoA and related compounds these cannot be built back up to glucose except via the glyoxalate shuttle these are called ketogenic Amino Acid metabolism p. 35 of 44 24 April 2008 Serine-based metabolites Serine is a building block for sphinganine and therefore for sphingolipids Serine also leads to phosphatidylserine, which is important by itself and can be metabolized to phosphatidylethanolamine and phosphatidylcholine Amino Acid metabolism p. 36 of 44 24 April 2008 Glycine-based metabolites porphobilinogen Glycine is a source for purines, glyoxylate, creatine phosphate, and (with the help of succinyl CoA) porphobilinogen, whence we get porphyrins, and from those we get chlorophyll, heme, and cobalamin Amino Acid metabolism p. 37 of 44 24 April 2008 We’ll continue amino acids next time… But first, a sneak preview of our coverage of nucleic acid chemistry, which we’ll do on Tuesday! Amino Acid metabolism p. 38 of 44 24 April 2008 6 5 Pyrimidines N 4 2 N 3 Single-ring nucleic acid bases pyrimidine 6-atom ring; always two nitrogens in the ring, meta to one another Based on pyrimidine, although pyrimidine itself is not a biologically important molecule Variations depend on oxygens and nitrogens attached to ring carbons Tautomerization possible Note line of symmetry in pyrimidine structure Amino Acid metabolism p. 39 of 44 1 24 April 2008