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4pp_8.Urea - a The urea cycle and amino acid catabollsm and...

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Unformatted text preview: a. The urea cycle and amino acid catabollsm and blosynthesls amino acids-‘7. I 3 The carbon chains are broken down to molecules Most mammals convert amino-acld nitrogen to . NH.‘ urea for excretlon _..' Sumo animals excrete NH.‘ or uric acid. most terrestrial fish a. other aquatic birds 5 reptiles vertebrates vertebrates : I 0 ; 9 a W: m H HzN-C-NHz 5 ammonium ion I >=o _ urea _" = ..... . .................... ‘m‘ Mum E H that feed into the TCA cycle. 1/14/2010 The urea cycle Hco,- 2 ATP 2 ADP + P, 0 D carhamoyl NHfM. HzN-ltli-O-llLO' "h“l’ha“ 0. citrulli no ornithino NH,‘ Pl 0 T”? | E i ll HzN'CHzCHch26H-Coz‘ HzN-c-NH-CHzCHzCHzCH-CO; m A» I ‘Ozc-cHch-NH; AMP + PPI co; 1an; rim; '01C-CHZCH-NH-C-NH-CHZCH,CHZCH-COI' argininosuccinate arginine lllllH,’ I:IH3' H2 N-C-NH-CH20HZCHZCH-Coz' -o,c-CH=CH-co,- tummy incorporation of ammonia Into urea begins with formation of carbaruoyl phosphate 9 0 NH; + H60; 7*: HzN-ltli-O-IP-O‘ “mam“ 0- phosphate 2 ATP 2 ADP + P] This occurs in the mitochondrial matrix. Carbamoyl-phosphate synthetase-l catalyzes the reaction in three steps, using two molecules of ATP: _ (1) E 9 _ carbani H603 H0 '0'?'0 phosphoricacid O_ anhydrida ATP ADP NHf (2) P. ATP ADP 9 5 4 E? 9 cathamate HzN-c-O- H2N-C-O-IP-O- (a) Q 1/14/2010 _ Arginlnosuccinate splits into arginine and fumarate Carbamoyl phosphate reacts with ornithine to form citrulllne 902'; m”? ’l‘le' ('3: 9 IF”; ‘02C-CHZCHfiH-C-NH-CHZCHZCHzCH-COZ‘ H N- - -P-O‘ . ' ' :- 1 06 ’HEN-CHZCHZGHch-coz ornlthlno .-' arginimsuccinate cariaamoyl I ‘ ' phosphate 9 ['qu: PI HzN-C-NH-CHZCHZCHZCH-COZ' 'DzC-CH=CH-COZ‘ + H+ citrulline lumarate NHZ’ NH3* II I HEN-C-NH-CHZCHZCHZGH-COZ‘ arginine This step also occurs in the mitochondrial matrix. This reaction occurs in the cytosol. Combination of citrulline with aspartate to form argininosuccinate is driven by breakdown of ATP to AMP Hydrolysis of arginlne releases urea and regenerates ornithine 002‘ 0 v”; ”Hf II'IH3+ I II . ‘Ozc-CHICH-NH,‘ HzN-C-NH-CHZCHZBHZCH-COZ‘ HzN'C'NH-CHzCHzCHzCH-Coz arginino aspartate ATP citrulline H20 AMP 4- PPI + H20 argininosuccinata 0 NH:‘ . ¢ 901 51'"! 5"”? HzN-Ei-NHZ HzN-CHz-CHz-CHZ-ICH-COZ' -o:c-CH2CH-NH-c-NH-CHZCH2cnch-coz- urea H’ ornithino This reaction occurs only in the cytosol, so citrulline first must leave the mitochondria. A transporter exchanges ornithine for This reaction occurs in the cytosol. To continue the citrulline plus a proton across the mitochondrial inner membrane. cycle, ornithine must return to a mitochondrion. G B \ carbamoyl citrulline _. .. NH: amiihifll " H2N-IC- NH-CH2CH2 CH2 :3H- -CO2 9 CO2 H2N-22-NH2 4...,:“ 1126 -CH 2CH-NH3‘ urea arginine ASP '3' co; NH2 IIIH3 _,‘O2C -CH2ICH-NH-"C-NH-CH2CH2 CH2I‘CH-CO2 argininosuccinate k Formation of urea consumes 4 phosphate anhydride bonds / Q The aspartate consumed in the urea cycle can be regenerated from the tumarate that is produced 2 ATP 2 ADP + P, H60; 52: carhamoyl + NH,‘ phosphate n-keto acids amino acids PE aspartate- oxal oacetatc ornithine aminotranslerase citrulline I tat oxa oace e ”m ATP cycle urea AMP + FF. malate dehydrogenase arginine argininosuccinate NADH malate f M tumarate :38 MD H2O This process also uses both oytosolic and mitochondrial enzymes 10 1/14/2010 K Oxidation of malate in mitochondria generates ATP 2 e’ to 02 via NADH dehydrogenase 4 -------- ...,._ 2 ATP 2 ADP + P‘ generates - 2.5 ATP ‘2. HBO ‘ carhamo I NADH u, 4 P VRNAD l M aspartate glutamate ornithine ' ' malate \ /' cItru\llme ckmmmmuflrate \ ornithine ci\:'ulline u-ketoglularate glutamate aspartate urea AMP + PP. _ _ amino acids a-ketoacids argInIne argininosuccinate malate tumarateL H2O but there are transporters for malate, aspartate, glutamate and a-ketoglutarate. NADH, MAD+ and oxaloacetate can’t cross the mitochondrial inner membrane, / 11 Transport systems in the mltochondrlal inner membrane exchange aspartate for glutamate and oI-ketoglutarate for malate aspartate- glmamate- + H' o-ketoglutarate malate aspartete- glutamate-4- H' a-ketogluta rate malate The Asp/Gin transporter can be driven by an electioch emical potential gradient because it also moves a proton across “In membrane. Mutations in this transporter have been linked to autism. 12 The or-ketoglutaratelmalate and aspartatelglutamate t:anspor1ers\ also participate In oxidation of cytosollc NADH [— oxaloa celete aspartate glutamate —>a-keteglutarate malate 2 e' to electron- transport chain as pa rtate glutamate 4— a-ketoglutarate malete LD nxaloacetate —n——J cytosol “AD" mu? - a. IIIIIII 'l-k-I/ k glycolysis / 13 The E coli lactose permease provides a model for other small-molecule transporters The entry to the cavity is open on this side cytepiasm 12 trans-membrane membrane u-helices surround a hydrophilic cavity periplasm closed on this side Lac permease transports a proton along with a fl-galactoside across the plasma membrane. J. Abramson et al., Science TDG = 1-thio-p-D-galactopyranoside 301161D(2003l luff-Dab 14 1/14/2010 The mitochondrial ATPIADP exchanger ltranslocase) also has a central cavity that opens to the solution on one side at the membrane atlactyloside (an inhibitor of ATPIADP exchange) 6 trans-membrane u-helices surround a cavity view normal to the membrane Elma“ The ATPlADP translocase is the most abundant protein in the mitochondrial inner membrane. H. Nury et at, FEBS Lett. 579: 6031 (20:35) It carries a Prom" into “19 matrix zcaepeh with each ATP-ADP exchange. 15 The urea cycle is regulated in two ways 1. Allosteric activation ofcarbanmylphosphate synthetase-l by N-acetylgiutamate CO . arginine CO . § . 2 g I = HEN-(li—H +acetyl-COA T CHaco-NH-(li—H N-acetylglutamate CH (EH2 GOA SH (EH2 Glu l 2 ' 9H2 002' (202' - Carbamoylphesphate synthetase-l is completely inactive in the absence of N-acetylGlu. - N-acetylGlu synthase is activated by arginine. - A genetic deficiency in N-acetylelu synthase can : carbamoyl- cause a lethal detect in the urea cycle. 7 phosphate - Aspecific hydrolase removes N-acetylGlu. 2 ATP 2 ADP + P, 5 ® 1‘. 9 9 NH,‘ +H003‘ HzN-C-O-f-O‘ O 2. A high-protein diet or starvation leads to increased synthesis of all five enzymes used in the urea cycle, including carbamoylphosphatne synthelase-l. Expression of N-acetylglulamate synthase also increases. 16 Inherited disorders of the urea cycle can have severe effects Defective Effects lncidence‘ enzyme carhamoylphosp hate lethargy, convulsions, < 0.5 synthetase-l early death argininosuccinic acidalnia, vomiting, 1.5 convulsions argininosuccinata lyase arginase arginemia, mental < 0.5 retard stion "Approximate incidence per 100,000 binhs People with these conditions can't be treated by simply removing proteins from their diet because humans are not able to synthesize all the necessary amino acids. Lahnlnger, Table 15-2 17 Autism is a neurodevelopmental genetic disorder - Deficits in verbal & nonverbal communication and social interactions - Repetitive or stereotyped behaviors - Incidence ~‘t per 1000 people (possibly 1 in 200) - Strong evidence for heritability - Polygenic — between 5 & 10 genes may be involved - Mutations of neuronal cell-adhesion molecules (cadherins) implicated K. Wang at al., Nature 459: 528 {2009) Single—nucleotide polymorphisms (SNPs) in the gene for a mitochondrial, Ca2‘-dependent Aspr'Glu exchanger increase the risk by a factor 01‘ 3 to 4. This is the main form of the AsplGlu exchanger that is expressed in the brain. Mutations in the gene impair the urea cycle. and could have other effects on mitochondrial metabolism. N. Rsmoz at sl.‘ Am. .1. Psychiatry 161: 562 (2004) L, Palmleri et ai, EMEO .r, 20: scsu (2001) 1/14/2010 Genetic deficiencies in some of the urea-cycle enzymes can be treated pharmacologically honzoats 01cm? Q/‘CCH phenylacolate ATP + GOA-SH ATP + GOA-SH MP+PPIJ a when) benzoyl-CoA @501" 5'6“ 0 phenylacstyl-CoA glycine glutamine CoA-si-i <1 0 CoA-SH :1: 0* " m 01 m 1 - H phenylacotyl- hippurate D glutamino (henzoylglycine) H2 The amide products of these reactions (hippurate and phenylacetylglutamine) are excreted in the urine. Synthesizing the Gly or Gin removes ammonia. is Arginine also serves as a precursor of nitric oxide (NO) ”H; 54H; arginine H2N-C-NH-CH26H20H26H-COZ' The enzyme nitric NADPH. 0; oxide synthase, which Hydroxyarginine "Amp. H20 catalyzes both steps, bound to on: me has four bound ( y ) cofactors: FMN, FAD, ill-OH 5‘le heme and [HZN'C'NH'CHZCHRCHZCH'Colj tetrahydrobiopterin 1r'2 NADPH, Oz . . I won’t expect you to N0 1": "ADP ’ H30 remember these details 0 or the structure of _ _ u hydrcxyarginine. citrullrne HzN-C-NH-CHZCHZCHZCH-COZ' N0 acts as a short-lived messenger in control of blood pressure, blood clotting. and neurotransmission. It binds to a guanylyl cyclase and activates production of c—GMP. 20 ‘ pyruvatei The carbon chains of the common amino acids Ieucine provide materials that feed Into the citric acid cycle lysine phenylalanine tryptophan tyrosine aoetoacetyl—coA ar Inlne isocitrate glgtamine / histidine citrate proline succinyl—CoA isoleucine leucine tryptophan isoleucine methionine threonine valine ‘ oxaloacetate l succinate alanine cysteine hen lalanine glycine - -' malate Imfla p y serine asparagine tyre e tryptophan ‘ . aspartate 21 . Amino acids can be classified leuclne . lysine as glucogenlc or ketogenic phenylalanine tryptophan tyrosine Some fall in both groups . . arginine Isoleuclne glutamine leuclne histidine threunlne proline tryptophan isoleucine methionine threonine a la nine cysteine glycine serine asparagine threonine aspartate tryptophan glucogenic 1/14/2010 Humans can synthesize 10 of the 20 common amino acids Amino acids that an organism cannot synthesize in adequate amounts undara given set of conditions are called l“essential." These that can be synthesized in adequate amounts are "nonessential." Mast bacteria and plants can synthesize all 2|) amino acids. Essential and Nonessentlal Amino Acids for Humans Essential Nonessential Arginine" Alanine Histidine Asparagine lsoleucine Aspartate Leucine Cysteine Lysine Glutamate Methionine Glutamine Phenylalanine Glycine Threonine Proline Tryptophan Serine Valine Tyrosine 'Arg is essential in iniants and growing children but not in adults. 23 Building blocks for synthesis of non-essential amino acids In humans come from glycolysis and the citric acid cycle giuccse L /' glycine 3-phosphoglycerate—. serine L x, cysteine pyruvate —. alanine citrate proiine oxalcacetate a-ketoglutarate—r glutamate _. glutamine aspartate \ J \‘arginine asparagine '\__ / 24 Serlne Is formed via 3-phosphoglycerate ca; ('20,- H-é-OH c=o éHz-o-® éHZ-o-® 3-p hosphuglycarata NAD’ NADH 3-phosphohyd mxypyruvata Glu b u-kG (202- ('20,- +H,N-é-H +H,N-c-H éHz-DH E ; éHro-® sorine pI ":0 3-phosphosnrine 25 1/14/2010 ...
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