Chap_22_2010_v3

Chap_22_2010_v3 - Chemical Aspects of Biological Systems...

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Unformatted text preview: Chemical Aspects of Biological Systems Information Pathways (142C/242C) Meetin g Time: Ins tru ctor: TR, 12: 30- 1:4 5 P M, Phelps H all 3 515 Prof. L u c J aeger Co ntact: jaeg er@ chem. ucsb.edu Office: P S BN 464 9A Office Hrs: R , 2 :00 -3:00 PM; by ap pointm ent wade (wg rabow@ chem.ucs b.e du) PSBN 46 38, P hone 5 302 TR (W ad e) : 1 1:00 AM-12:00 AM an d by a ppointment TA: TA Office Hours : http://www.chem.ucsb.edu/coursepages/index.shtml Username: chem_142c and Password: chem_242c C. Oxaloacetate and Pyruvate amino acids families 1 step 1 step 7 steps 9 steps 5 steps Essential aa Essential aa Essential aa Essential aa Essential aa Essential aa 4 steps 1 step 7 steps 4 steps 1 Synthesis of the 3 non-essential amino-acids from oxaloacetate and pyruvate Transami nation (from Glu) Transami dation (from Gln ) nonessential aa nonessential aa nonessential aa Transami nation (from Glu) Formation of Asp and Ala by transamination from Glu or Oxaloacetate or Aspartate 2 Formation of Asparagine from Asp and Gln Asparagine synthetase is a kind of amidotransferase Need ATP! Reminder from past lecture! Transfer of amino groups derived from the amide nitrogen of Gln Proposed mechanism for amido-transferase Conserved Cys X= phosphoryl group 3 Thr, Lys and Met are derived from Asp 4 C, 1 N from Asp Aspartokinase 5 steps Threonine Isoleucine Threonine synthase Aspartate β-semialdehyde dehydrogenase Homoserine kinase 7 steps Lysine Homoserine dehydrogenase 4 steps Methionine Biosynthesis of methionine from homoserine Homoserine acyltransferase Cystathionine β-lyase Cystathionine γ-synthase Methionine synthase Methionine 4 C, 1 N from Asp S from Cys 4 Biosynthesis of lysine from Aspartate β-semialdehyde (1st part) Dihydropicolinate synthase Dehydrogenase Synthase Aminotransferase Biosynthesis of lysine from Aspartate β-semialdehyde (2nd part) 3 or 4 C from Asp 3 or 2 C from pyruvate 1 N from Glu Desuccinylase Epimerase Decarboxylase Lysine 5 Relationship between the various amino acids related to the Asp pathway Aspartate Pyruvate Glutamate α- ketoglutarate 7 steps Homocysteine Isoleucine 4 steps α- ketobutyrate Aspartate β- semialdehyde Threonine Methionine Lysine Pyruvate Serine Cystathionine Succinate Homoserine O- Succinylhomoserine Note the interlocking points with the pyruvate pathway and serine pathway. α- ketobutyrate Cysteine Biosynthesis of Ile, Val and Leu from pyruvate Asp pathway Aceto -lactate synthase Acetohydroxy acid isomeroreductase The same enzymes are responsible for the synthesis of Ile and Val 6 dihydroxy acid dehydratase (4 steps) Leucine Valine aminotransferase Isoleucine Valine Isopropylmalate synthase Isomerase Dehydrogenase Leucine aminotransferase Leucine 7 Amino acid biosynthesis is under allosteric regulation (General principles) Enzymes multiplicity (isozymes) (like inhibition of glu synthetase) Concerted inhibition Irreversible reaction Multiple, overlapping negative feedback inhibition Sequential feedback inhibition Feedback inhibition of the first reaction in a sequence D. Aromatic amino acids family Essential aa Essential aa Tyr is not an essential amino acid as it can be synthesized from Phe. Aromatic rings are not readily available in the environment. The main biological route of aromatic ring formation is through the following pathway. 8 Chorismate is a key intermediate in the synthesis of Trp, Phe and Tyr. synthase First 4 steps: -> formation of shikimate dehydratase dehydrogenase shikimate Formation of chorismate from shikimate shikimate synthase kinase synthase Phe (3 steps) Tyr (3 steps) Trp chorismate (5 steps) 9 (1) Chorismate mutase (2) Prephenate dehydratase In plants and bacteria (3) Aminotransferase (1) Chorismate mutase (2) Prephenate dehydrogenase In plants and bacteria (3) Aminotransferase 10 In animals, Tyr can be produced from Phe by phenylalanine hydroxylase Tyrosine Tyrosine is thus considered nonessential 11 E. Histidine family H Essential aa Histidine biosynthesis 3 steps 2 steps 2 steps dehydratation & transamination 12 F. Molecules derived from amino acids => (In animals) Glycine is a precursor of porphyrins (In bacteria and plants), Glutamate is the precursor (glu-tRNAglu) Porphyrins nucleus in heme proteins (e.g cytochromes, hemoglobin…) Heme is the source of bile pigments => Gly, Arg and Met are the precursor of creatine Gly, Arg and Met -> creatine and ATP -> phosphocreatine Phosphocreatine is an important energy buffer in muscle => Glu, Cys an Gly are the precursor of glutathione (γGlu-Cys-Gly) Glutathione (GSH) can be seen as a redox buffer, as helping to maintain the SH group in the reduced state and iron in the ferous (Fe2+ ) state, reducing agent for glutaredoxin in dNMP synthesis, as contributing to remove toxic peroxides (with Glutathione peroxidase). 2 GSH + R-O-O-H -> GSSG + H2O + R-OH F. Molecules derived from amino acids => Aromatic amino acids are precursors of many plant substances Phe + Tyr -> Lignin (rigid plant polymer) Trp -> Auxin (plant growth hormone) => Several biological amines are product of amino acid decarboxylation => neurotransmitters (a) Tyr -> dopamine -> nonephrine -> epinephrine (b) His -> histamine (c) Trp -> serotonin (d) Glu -> γ-aminobutyrate (GABA) => Polyamines => Met and Ornithine -> spermidine -> spermine => Nitric oxide (NO*) secondary messenger produced from Arg 13 Part 4: biosynthesis of nucleotides Part 4: biosynthesis of nucleotides Things to know!!! De novo synthesis of purine nucleotides -> purine ring of inosinate is synthesized on the ribose phosphate -> Inosinate (IMP) is synthesized from PRPP, Gly, Gln , Asp, CO2 and formate -> IMP is the precursor of AMP and GMP De novo synthesis of pyrimidines nucleotides -> The pyrimidine is constructed from Asp and carbamoyl phosphate to form first orotate . -> Orotate reacts with PRPP to form orotidylate . -> Decarboxylation of orotidylate leads to UMP. -> CTP is synthesized form UTP. 14 Amidotransferases 15 Synthesis of AMP and GMP from IMP Amidotransferase De novo synthesis of pyrimidines nucleotides -> The pyrimidine is constructed from Asp and carbamoyl phosphate to form first orotate . -> Orotate reacts with PRPP to form orotidylate . -> Decarboxylation of orotidylate leads to UMP. -> CTP is synthesized from UTP. 16 Urea cycle and related reactions Arginase One of the amino group of urea comes from Carbamoyl phosphate, the other comes from Aspartate 17 Reaction catalyzed by the cytosolic carbamoyl phosphate synthetase II (identical as the one of carbamoyl phosphate synthetase I from mitochondria). In bacteria, only carbamoyl phosphate synthetase for the synthesis of Arg and pyrimidine. De novo synthesis of pyrimidines nucleotides Allosteric regulation aspartate transcarbamoylase by CTP and ATP 18 Reduction of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase 19 Reduction of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase Ribonucleotide reductase 20 21 Biosynthesis of deoxy-thymidylate from deoxy-uridylate Thymidylate synthase The methyl in C5 of thymine is coming from serine! = The methyl in C5 of thymine is coming from serine! 22 Salvage pathways 23 ...
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