Metabolismo de Nucleótidos: Reacciones Bioquímicas Clave en Biología

Metabolismo de Nucleótidos

TEMA 1. METABOLISME DE NUCLEOTIDS Dr. Joan GilDonat el caracter i la finalitat exclusivament docent i eminentment il·lustrativa de les explicacions a classe d'aquesta presentació, l'autor s'acull a l'article 32 de la Llei de propietat intel lectual vigent respecte de l'ús parcial d'obres alienes com ara imatges, gràfics o altre material contingudes en les diferents diapositives Totes les imatges presentades s'inclouen com a cites necessaries per il·lustrar les explicacions d'aquesta classeThe base may be either a pyrimidine or a purine.

Base Base P Base + + P = Phosphate Nucleotide Pyrimidines NH, I C HC N HC C N H Cytosine (C) HỌC NH HC N H Thymine (T) C RNA C C ANH HC. Uracil (U) Purines NH2 1 N N HO C CH N N H Adenine (A) O C NH HC C N `NH2 H Guanine (G) dna C C C N Ribose or deoxyribose Nucleoside

Nomenclatura de Bases, Nucleósidos y Nucleótidos

Nomenclatura de Bases, Nucleósidos y Nucleótidos en RNA

TABLE 25.1 Nomenclature of bases, nucleosides, and nucleotides RNA Base Ribonucleoside Ribonucleotide (5'-monophosphate) Adenine (A) Adenosine Adenylate (AMP) 3mN Guanine (G) Guanosine Guanylate (GMP) Uracil (U) Uridine Uridylate (UMP) 0,4 Cytosine (C) Cytidine Cytidylate (CMP)

Nomenclatura de Bases, Nucleósidos y Nucleótidos en DNA

DNA fosfato Base Deoxyribonucleoside Deoxyribonucleotide (5'-monophosphate) Adenine (A) Deoxyadenosine Deoxyadenylate (dAMP) Guanine (G) Deoxyguanosine Thymine (T) Thymidine 15microMDeoxyguanylate (dGMP) Thymidylate (TMP) Cytosine (C) Deoxycytidine Deoxycytidylate (dCMP)The base may be either a pyrimidine or a purine.

Base Base P = Ribose or deoxyribose Nucleoside Phosphate Nucleotide Pyrimidines NH, I C HC N HC C N H Cytosine (C) HỌC NH HC N H Thymine (T) 0= C C ANH HC. Uracil (U) Purines NH2 1 N N HO C CH N N H Adenine (A) O C ÌNH HC C C N N `NH2 H Guanine (G) Base + + P C C

Vías de Síntesis de Nucleótidos

Vía de Recuperación (Salvage Pathway)

SALVAGE PATHWAY Activated ribose (PRPP) + base Nucleotide

Vía De Novo

DE NOVO PATHWAY Activated ribose (PRPP) + + + + . . . Nucleotides

Síntesis de Fosforribosil Pirofosfato (PRPP)

intesis fosforribosil 5 2-03POH2Ç O ATP AMP 1 OH PRPP synthetase HO OH Ribose 5-phosphate PRPP Unnumbered 25 p739a Biochemistry, Seventh Edition @ 2012 W. H. Freeman and Company 2-O3POH2C O O O O o 2- P P === O O O HO OH I

Estructura de Pirimidinas

Pyrimidines NH2 C HC N HC Cytosine (C) H3C =U NH HC Thymine (T) =( NH HC Uracil (U)

Síntesis de Bases Pirimidínicas

Componentes y Control de la Síntesis de Pirimidinas

sintesis bases pirimidinicas: aa, N se sintetizan independientemente?se comparte q comp. utilizan las celulas?

Síntesis De Novo de Nucleótidos de Pirimidinas

sintesis de novo de nucl. pirimidinas Bicarbonate carbamilfosfato sintetasa + NH4 --- glutamina 2 ATP Carbamoyl phosphate Aspartate N C 4 .C 3 5 C2 6C 1 N Pyrimidine ring PRPP (a ribose phosphate) oxi UTP CTP to RNA desoxi TMP dCTP to DNA

Primera Etapa de Síntesis de Pirimidinas

1 etapa Glutamine ATP ADP 0 2- NH3 P 0 - II P C HO HO tapa O Bicarbonate Carboxyphosphate Carbamic acid ATP ADP 2- 0 O O O= II C .P C O HO NH2 2 O O NH2 Carbamic acid Carbamoyl phosphate

Actividades Enzimáticas en la Síntesis de Pirimidinas

como es posible q una mole. tenga 3 actividades? mas de un centro activo C O HO NH2 0 OGlutamine hydrolysis site Glutamine NHẸ Bicarbonate phosphorylation site 5 Carbamic acid Carbamoyl phosphate Carbamic acid phosphorylation site Figure 25.3 Biochemistry, Seventh Edition @ 2012 W. H. Freeman and Company

Síntesis de Orotato

sintesis orotato O O O + 2- 0 Aspartate C H+ H2O C 0 U Pi HN NH2 U HM NH U HN NH -P C -OOC O NH2 COO- dihidroorotasa O dihiorotato deshidrogenasa O HH H Carbamoyl phosphate Carbamoylaspartate Dihydroorotate Orotate *en 1 sola cadena polipeptidica.(controlamos 5 act. dif.) brequinar inhibidor de hidroorotato desh. en ensayo terapia sars cov-2 C NAD+ H+ O aspartato transcarbamilasa H HH NADH

Síntesis de Orotidilato

sintesis orotidilato a partir de orotato y prpp O HŅ -O O N H O Orotate + 2-OzPOH2C O O O 0 O 2- P- P= O O O HÓ OH 5-Phosphoribosyl-1-pyrophosphate (PRPP) fosforibosil transferasa de pirimidinas PP HN O 2-OzPOH2C O C-O - O HÓ OH Orotidylate

Síntesis de Nucleótidos de Pirimidina a partir de Orotidilato

sint. nuel de pirimid apartir de orotidilato O HN HN O 2-OzPOH2C N 2-OzPOH2C N O orotidilato descarboxilasa H CO - O HO OH HO OH Orotidylate Uridylate H+ CO2 O 1 OGln + H20 0 Glu N O 4-OzPOJPOʒPOH2C N O H ATP ADP + HO OH HÓ OH ctp sintetasa UTP СТР NH2 HN NH3 4-OzPOzPOJPOH2C N .O Pi

Control de la Síntesis de Nucleótidos de Pirimidina

control sint. nucleot. pirimid. O 2- 0 0 Aspartate Pi U C H+ H2O C NAD+ H+ C HN NH -P C O NH 2 COO- O H H O "OOC O HH H Carbamoyl phosphate Carbamoylaspartate Dihydroorotate Orotate CTP NADH O O + II HN NH2 U HM NH "OOC- HH

Vías de Síntesis de Nucleótidos (Revisión)

Vía de Recuperación (Salvage Pathway)

SALVAGE PATHWAY Activated ribose (PRPP) + base Nucleotide

Vía De Novo

DE NOVO PATHWAY Activated ribose (PRPP) + amino acids + ATP + CO2 + . . . Nucleotide

Estructura de Purinas

Purines NH2 N N HC I HC CH N N H H N NH2 Adenine (A) N ( NH N Guanine (G)

Síntesis de Bases Púricas

Componentes y Control de la Síntesis de Purinas

como se podrian sintetizar bases puricas? cuales podrian ser los compuestos q utilizan celulas?!!! CO2 Glycine 4 2 Aspartate 5 C 6 5 C N 7 N10-Formyl- tetrahydrofolate 8C 3 I-II 6 c2 Ʒ N 1 4℃ 9 NE1 Glutamine ribose-P Glutamine IMP III p. de control ATP GTP to RNA dATP desoxi dGTP to DNA como se controlaria esta via? los productos y sustratos. N10-Formyl- tetrahydrofolate 7 Purine ring structure N 12-03POH2C O HO OH PRPP Glu + NH3 1 + PP Gin + H2O 2-O3POH2C NH2 HO OH 5-Phosphoribosyl-1-amine 1 2 3 O O ATP ADP + + Gly P H CH2 > P-ribose Phosphoribosyl- amine Glycinamide ribonucleotide Formylglycinamide ribonucleotide +++ Glu Gin Formylglycinamidine ribonucleotide ATP 4 ADP ATP + + P H 2 N + O P-ribose P-ribose € P-ribose 5) NH2 5-Aminoimidazole ribonucleotide 7 H -N coo" Fumarate Ń CH2 P-ribose® N-CH NH2 H C=0 O 5-Aminoimidazole- 4-(N-succinylcarboxamide) ribonucleotide 5-Aminoimidazole- 4-carboxamide ribonucleotide Step Enzyme 1 Glycinamide ribonucleotide (GAR) synthetase 2 GAR transformylase 3 Formylglycinamidine synthase 4 Aminoimidazole ribonucleotide synthetase 5 Carboxyaminoimidazole ribonucleotide synthase 6 Succinylaminoimidazole carboxamide ribonucleotide synthetase 7 Adenylosuccinate lyase 8 Aminoimidazole carboxamide ribonucleotide transformylase Inosine monophosphate cyclohydrolyase H. H N CH THE THF Z > P-ribose NH, NH2 -N H O 5-Formaminoimidazole- 4-carboxamide ribonucleotide 9 H2O I N P-ribose NH H Inosinate (IMP) IZ CH2 CH2 P-ribose P-ribose H3N H2O ·H H .H N + Nº ATP P 1 P-ribose-NH2 ATP + Carboxyaminoimidazole ribonucleotide Asp 6 ADP + .H P O 8 O ADP H N .Caso P HO C-H Ň C-H NH2 HN > P-ribose NH H 9 ADP NH2+ THE H THF 2 H H

Enzimas de la Síntesis De Novo de Purinas

Tabla de Enzimas de Síntesis de Purinas

Table 25.2 The enzymes of de novo purine synthesis Step Enzyme 1 Glycinamide ribonucleotide (GAR) synthetase 2 GAR transformylase 3 Formylglycinamidine synthase 4 Aminoimidazole ribonucleotide synthetase 5 Carboxyaminoimidazole ribonucleotide synthase 6 Succinylaminoimidazole carboxamide ribonucleotide synthetase 7 Adenylosuccinate lyase 8 Aminoimidazole carboxamide ribonucleotide transformylase 9 Inosine monophosphate cyclohydrolyase Table 25.2 Biochemistry, Seventh Edition @ 2012 W. H. Freeman and Company 1,2,4 una solc cad. polip. en eucariotas superiores tambien 5, y 6

Enzimas de la Síntesis De Novo de Purinas (Continuación)

Table 25.2 The enzymes of de novo purine synthesis Step Enzyme 1 Glycinamide ribonucleotide (GAR) synthetase 2 GAR transformylase 3 Formylglycinamidine synthase 4 Aminoimidazole ribonucleotide synthetase 5 Carboxyaminoimidazole ribonucleotide synthase 6 Succinylaminoimidazole carboxamide ribonucleotide synthetase 7 Adenylosuccinate lyase 8 Aminoimidazole carboxamide ribonucleotide transformylase 9 Inosine monophosphate cyclohydrolyase Table 25.2 Biochemistry, Seventh Edition @ 2012 W. H. Freeman and Company

Síntesis de 5-Fosforribosil-1-amina

sintesis de 5 prpp 1 - amina 2-03POH2C C O O O 2- P. P === O O O HO OH PRPP 5-Fosforribosil-1-pirofosfat Glu + NH3 glutamina- fosforibosilamidottransferasa PP¡ Gln + H2O 2-03POH2C NH2 O HO OH 5-Phosphoribosyl-1-amine

Síntesis De Novo de Nucleótidos de Purina (Detallado)

sintesis de novo de nucleotidos de purina formiltetrahidrofolato prpp gln -- PPi glu 1 2 3 O O 0 C H .H + ATP Pi N. CH2 N CH2 P-ribose-NH2 P-ribose C P-ribose Ö H3N H2O Phosphoribosyl- amine Glycinamide ribonucleotide Formylglycinamide ribonucleotide +++ Glu Gln Formylglycinamidine ribonucleotide ATP 4 ADP **** ATP + 6 + + H -N -N formil CON Z + C == C N N P-ribose O NH HN C=0 NH2 - O 5-Aminoimidazole ribonucleotide ATP + Asp 6 ADP + Pi H C- aspartato O N CH2 P-ribose C N-CH NH2 H C=0 - O 5-Aminoimidazole- 4-(N-succinylcarboxamide) ribonucleotide no saber solo como se hace 1 Glycinamide ribonucleotide (GAR) synthetase gto ATP 2 GAR transformylase 3 Formylglycinamidine synthase 4 Aminoimidazole ribonucleotide synthetase 5 Carboxyaminoimidazole ribonucleotide synthase 6 Succinylaminoimidazole carboxamide ribonucleotide synthetase + + ŅH3+ Gly Pi THE H THF H N CH2 1 P-ribose® N H *** en mamiferos no requiere ATP O ADP H C= C= P: HO C-H N P-ribose C P-ribose C 5 Carboxyaminoimidazole ribonucleotide C ATP ADP ADP H .H = N Nº sintasa no tiene porque gastar ATP O == U H C-H

Folatos y sus Derivados

Estructura de Ácido Fólico y Derivados

FOLATOS Derivado d acido folico Vitamina B9 N N H2N 8 CH 2 7 3 6 9 N 4 5 CH2 N O COOH OH HN C-N-CH-CH2-CH2-COOH -I Pteridine para-aminobenzoic acid Glutamic acid Pteroyl glutamic acid H 1 N N H2N CH2 7 H N CH2 N O COOH OH HN C-N-CH-CH2-CH2-COOH H Dihydropteroyl glutamic acid (Dihydrofolate) H 1 N N. H2N CH2 H N CH2 N O COOH OH H HN C -N-CH-CH2-CH2-CO OH H Tetrahydropteroyl glutamic acid (Tetrahydrofolate) H N N H2N CH2 5 H N CH2 - OH CH3 HN CH-CH2-CH2-COJOH metil H 5-methyl tetrahydrofolate H N N H2N CH2 H N CH2 - OH HN CN-CH-CH2-CH2-CO OH H 10 CHO 10-formyl tetrahydrofolate - I N COOH N COOH 10 1H I-Z V N H2N CHP H N CH2 N COOH OH I HN C -- N-CH-CH -- CH -- CO OH In H CHO 10-formyl tetrahydrofolate

Conversión a Inosinato (IMP)

O H -N O .N. 0 CH2 P-ribose C N-CH 7 NH2 H C-O O 5-Aminoimidazole- 4-(N-succinylcarboxamide) ribonucleotide 7 adenilocucinato liasa 8 aminoimadazol caboxamida ribonuc transformialsa 9 inosina monofostado ciclo hidrolasa 5-Aminoimidazole- 4-carboxamide ribonucleotide ZMP H N C O H20 C N C P-ribose U 1 P-ribose C NH2 H N 9 N: H C C H Ò 5-Formaminoimidazole- 4-carboxamide ribonucleotide Inosinate (IMP) 8 NH2 H ·N C- O THF H THE N P-ribose C NH 2 O H coo Fumarate 0= H -N O C N NH H -! proceso, idea.

Síntesis De Novo de Purinas (III)

sint. de novo purinas (III) GTP .H ..... HN N COO- H COO- GDP N + GTP Pi + P-ribose P-ribose N Asp Adenylsuccinate N adenilsuccinato sintasa NH N- P-ribose Z .N N AMP 2 enlaces del ATP NH ATP PP¡ N Inosinate NAD+ + N N NADH N P-ribose N H NH2 oxidacion-reduccion H+ Xanthylate HẸN H2O Guanylate (GMP) + + Glu Gln gln donador grupo amino NH2 .N. N N N- N adenilsuccinato liasa O Adenylate (AMP) C H20 P-ribose + O IMP DESHIDROGENASA TOOC. H Fumarate