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UMPOLUNG in REACTIONS CATALYZED by THIAMINE PYROPHOSPHATE DEPENDENT ENZYMES Umpolung En Reacciones Catalizadas Por Enzimas Dependientes De Pirofosfato De Tiamina

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UMPOLUNG in REACTIONS CATALYZED by THIAMINE PYROPHOSPHATE DEPENDENT ENZYMES Umpolung En Reacciones Catalizadas Por Enzimas Dependientes De Pirofosfato De Tiamina Ciencia, Ambiente y Clima, Vol. 2, No. 2, julio-diciembre, 2019 • ISSN (impreso): 2636-2317 • ISSN (en línea): 2636-2333 DOI: https://doi.org/10.22206/cac.2019.v2i2.pp27-42 UMPOLUNG IN REACTIONS CATALYZED BY THIAMINE PYROPHOSPHATE DEPENDENT ENZYMES Umpolung en reacciones catalizadas por enzimas dependientes de pirofosfato de tiamina Carlos José Boluda Emily Soto Instituto Tecnológico de Santo Domingo (INTEC), Instituto Tecnológico de Santo Domingo (INTEC), Área de Ciencias Básicas y Ambientales, Av. de Los Área de Ciencias Básicas y Ambientales Próceres 49, Santo Domingo, República Dominicana Correo-e: [email protected] *Corresponding author: Carlos J. Boluda Darah de la Cruz Correo-e: [email protected] Instituto Tecnológico de Santo Domingo (INTEC), Carolina Juncá Área de Ciencias Básicas y Ambientales Instituto Tecnológico de Santo Domingo (INTEC), Correo-e: [email protected] Área de Ciencias Básicas y Ambientales Anny Peña Correo-e: [email protected] Instituto Tecnológico de Santo Domingo (INTEC), Área de Ciencias Básicas y Ambientales Correo-e: [email protected] Recibido: 25/9/2019 • Aprobado: 19/10/2019 Cómo citar: Boluda, C. J., Juncá, C., Soto, E., de la Cruz, D., & Peña, A. (2019). Umpolung in reactions catalyzed by thiamine pyrophos- phate dependent enzymes. Ciencia, Ambiente Y Clima, 2(2), 27-42. Doi: https://doi.org/10.22206/cac.2019.v2i2.pp27-42 Abstract Resumen The temporal exchange of the electrophilic/nucleophilic El intercambio temporal del carácter electrofílico/nucleofí- character of an atom by chemical manipulation is known lico de un átomo mediante manipulación química, es cono- in organic chemistry as umpolung. This inversion of polarity cido con el vocablo alemán de umpolung. Esta inversión de allows the exploration of new synthetic possibilities which polaridad permite explorar nuevas posibilidades sintéticas cannot be achieved from the normal reactivity of functional que no pueden llevarse a cabo partiendo de la reactividad groups. It is not only a useful synthetic tool, but it is also normal de los grupos funcionales. Se trata de una herra- utilized by certain enzymes during biochemical reactions mienta sintética útil, que también es utilizada por ciertas in living organisms. Thiamine pyrophosphate dependent enzimas en determinadas reacciones bioquímicas que enzymes, such as pyruvate decarboxylase, pyruvate dehy- tienen lugar en las células. Las enzimas dependientes del drogenase, α-ketoglutarate dehydrogenase, branched-chain pirofosfato de tiamina, como la piruvato descarboxilasa, la α-keto acids dehydrogenase and transketolase, provide clear piruvato deshidrogenasa, la α-cetoglutarato deshidrogenasa, examples of umpolung in cellular reactions that fulfill dif- la deshidrogenasa de α-cetoácidos de cadena ramificada y la ferent purposes. In this review, after a discussion regarding transcetolasa, proporcionan ejemplos claros de umpolung the meaning of the term umpolung found in the chemical en reacciones celulares. En esta revisión, tras una discusión literature, the reaction mechanisms and the biochemical sobre el significado del términoumpolung encontrado en la meaning of transformations carried out by the aforemen- literatura química, se analizan los mecanismos de reacción tioned enzymes are analyzed. y el significado bioquímico de las transformaciones llevadas a cabo por las enzimas mencionadas. Keywords: dehydrogenase; decarboxylase; thiamine pyro- phosphate; transketolase; umpolung. Palabras clave: deshidrogenasa; descarboxilasa; pirofosfato de tiamina; transcetolasa; umpolung. | 27 Esta obra está bajo licencia internacional Creative Commons Atribución-NoComercial-CompartirIgual 4.0 Internacional Carlos José Boluda, Carolina Juncá, Emily Soto, Darah de la Cruz y Anny Peña 1. Introduction ophile). This can be observed in reactions such as the Claisen condensation between acetyl-CoA and Multiple reactions in cellular metabolism consist in oxaloacetate (OAA), catalyzed by citrate synthase C-C bond formation or breakage. During glycol- during the Krebs cycle. In this reaction, both the ysis, the retro-aldol reaction catalyzed by aldolase, carbonyl group and the enolate keep their typ- in which the fructose-1,6-diphosphate splits in two ical reactivity, them being electron acceptor and phosphorylated trioses, represents an example of electron donor, respectively (Nelson, Cox & Leh- C-C bond cleavage. ninger, 2013). Figure 1 shows the enolate of ace- tyl-CoA (1) reacting with the carbonyl group of Usually, the linkage of carbons occurs between the OAA (2) to form a new C-C bond in the citrate atoms with opposite polarities (electrophile/nucle- molecule (3). Figure 1. Nucleophilic attack of enolate to oxaloacetate (OAA) in citrate synthase reaction mechanism. Note: Acetyl-CoA (1), OAA (2), citrate (3), coenzyme A (4). (a): acceptor (electrophile); (d): donor (nucleophile). Dashed arrows represent the involvement of several steps. The Citroyl-CoA intermediate thioester formation has be en omitted. The formation of C-C bonds between carbons shar- non-oxidative phase of the pentose phosphate. In ing the same polarity is also possible. Nevertheless, the latter, as shown in Figure 2, a C-2 fragment it requires the reversal of the electron donor/accep- must be transferred from a ketopentose (4) to an tor character of one of the atoms, a phenomenon aldopentose (5), resulting in a ketoheptose (6) known as umpolung. The carbonyl group is intrin- and a triose (7). This reaction is catalyzed by the sically an acceptor, and therefore reacts with elec- transketolase, a thiamine pyrophosphate (TPP) tron donors and not with another electron deficient dependent enzyme which belongs to a diverse carbons. Examples of reactions between carbonyl group of biocatalysts involved in the rupture and/ groups to form a C-C bond are found in meta- or formation of C-C bonds (Mosbacher, Mueller bolic pathways such as the Calvin cycle and in the & Schulz, 2005). 28 | Ciencia, Ambiente y Clima 2019; 2(2, julio-diciembre): 27-42 • Artículos originales Umpolung in reactions catalyzed by thiamine pyrophosphate dependent enzymes Figure 2. A step in the non-oxidative phase of the pentose phosphate pathway. Note: Xylulose-5-phosphate (4), ribose-5-phosphate (5), sedoheptulose-7-phosphate (6), glyceraldehyde-3-phosphate (7). TK: transketolase, (a): acceptor. The objective of this review is to illustrate how the from the original reactivity of its functional group inversion of the original polarity of the carbonyl (Eymur, Göllü & Tanyeli, 2013). The Corey-See- group in certain cellular metabolites takes place bach reaction is a classic example of umpolung in inside the active site of TPP-dependent enzymes. which the inversion of the normal reactivity of a car- Additionally, the biochemical meaning of these inver- bonyl group (electrophile) is produced. This allows sions is analyzed. the carbonyl carbon to react with electrophiles as an acyl anion, exhibiting the opposite chemical behav- 2. Umpolung ior of its natural reactivity and being very useful in organic synthesis (Corey & Seebach, 1965). Umpolung is a German word, used since the mid-twentieth century (Wittig, Davis & Koenig, As shown in Figure 3, in the Corey-Seebach reaction 1951; Seebach & Corey, 1975), that refers to any the treatment of 1,3-dithianes (9) with n-butyl-li- process by which the nucleophilic (electron donor) thium leads to a carbanion (10) with an excellent or electrophilic (electron acceptor) character of an nucleophilic reactivity (Corey & Seebach, 1965). atom in a molecule is exchanged (Seebach, 1979). The carbanions thus formed can be used in multiple This inversion of the atoms inherent polarity allows reactions in which a new bond is formed between the carrying out of reactions that are not possible two originally electrophilic carbons. Figure 3. The Corey-Seebach reaction. Note: Treatment of aldehyde (8) with 1,3-propanedithiol yields a 1,3-dithiane (9). The carbanion obtained by treatment of (9) with n-buthyl-lithium reacts with an electrophile (E+) to form a new carbon-carbon bond (11). The removal of the dithiane protecting group leads to a ketone (12). (a): acceptor; (d): donor. Ciencia, Ambiente y Clima 2019; 2(2): 27-42 • Artículos originales | 29 Carlos José Boluda, Carolina Juncá, Emily Soto, Darah de la Cruz y Anny Peña The Corey-Seebach reaction has been widely used in strategy used by Noda and Watanabe in the enan- natural product synthesis (Yus, Nájera & Foubelo, tiospecific synthesis of the (R)- and (S)-enantiomers 2003). Figure 4 shows the conjugate addition of a of a flavanone. The nucleophilic addition of the lithiated dithiane derived from (14) to 2-furanone; carbanion of a dithiane (17) to a chiral epoxide forms this sequence of reactions has been employed in a diol (18) that under Mitsunobu cyclization yields (±)-podorhizol, (±)-isopodophyllotoxone (Ziegler the synthetic target (19) (Noda & Watanabe, 2002). & Schwartz,1978) and in arylnaphtalene lignans The dithianes have also been used to obtain more synthesis (González, Pérez & Trujillo, 1978; Boluda, complex natural products as spongistatins (Smith et López, Pérez & Trujillo, 2005). Figure 5 shows the al., 2001). Figure 4. Conjugate addition of a lithiated dithiane derived from (14) to a 2-furanone. Note: Conjugate addition of the aryl dithiane anion of compound (14) to 2-furanone yielding the corresponding enola- te, which leads to the compound (15) by protonation. Further steps lead to (±)-isopodophyllotoxone (16). Figure 5. Strategy used in the enantiospecific
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