UNIVERSIDAD LA SALLE FACULTAD DE CIENCIAS QUMICAS

LICENCIATURA EN QFB
BIOQUMICA DE MACROMOLCULAS TRABAJO: PPTIDOS CCLICOS
ALUMNA: GMEZ RIVERA YOLANDA

_________________ DR. JOS D. MNDEZ

___________ CALIFICACIN

FECHA: 10-Octubre-2011

PPTIDOS CCLICOS
INTRODUCCIN Un pptido que forma una estructura de anillo; tyrocidin A, un antibitico, es un decapptido cclico; valinomicina es un depsipptido cclico. Diversas familia de pptidos cclicos revisten una alta importancia debido a su actividad inmunosupresora (ciclosporinas), antibitica (gramicidinas) o txica (microcistinas). La ionizacin de un pptido cclico no presenta ningn problema adicional respecto a un pptido lineal. Las ciclosporinas y ramicidinas han sido utilizadas extensivamente como compuestos de test de nuevos sistemas de EM. En el caso de secuencias que contienen slo aminocidos apolares, como las ciclosporinas, la eliminacin del amino y carboxilo terminal en el pptido cclico confiere a la molcula la suficiente volatilidad para su anlisis directo por impacto electrnico y de hecho este ha sido el mtodo utilizado inicialmente para la determinacin del peso molecular de las ciclosporinas o en los primeros estudios de fragmentacin de estos pptidos. La elucidacin de la secuencia de aminocidos en un pptido cclico no puede hacerse sin embargo en la misma a que para un pptido lineal. La rotura competitiva de los diferentes enlaces en la cadena peptdica origina, en el caso de pptidos lineales, fragmentos de distinta longitud que permiten asignar la secuencia. Sin embargo, en el caso de pptidos cclicos estas fragmentaciones originan una mezcla de iones lineales (iones acilo) que poseen todos los mismos pesos moleculares y que a su vez pueden seguir fragmentando. A medida que el tamao de la molcula aumenta, el espectro se hace a su vez ms complejo. Esta especial caracterstica hace que los pptidos cclicos requieran estrategias especficas para su secuenciacin, especialmente teniendo en cuenta la no aplicabilidad de los mtodos de degradacin de Edman al pptido intacto. La solucin clsica consiste en la utilizacin de la EM para la determinacin del peso molecular del compuesto y la utilizacin del RMN como tcnica bsica para la elucidacin estructural. La baja sensibilidad y la incapacidad de los mtodos de RMN para el anlisis de mezclas ha originado sin embargo un activo trabajo en torno al desarrollo de mtodos basados en la EM. (David Andreu) CLASIFICACIN Los pptidos cclicos se clasifican principalmente en pptidos cclicos homodticos y pptidos cclicos heterodticos. A continuacin se muestra la informacin sin traduccin para evitar una mala interpretacin del texto. Homodetic Cyclic Peptides Cyclic peptides in which the ring consists solely of amino-acid residues in eupeptide linkage may be called homodetic cyclic peptides. Three representations are possible: (Moss) The sequence is formulated in the usual manner but placed in parentheses and preceded by 'cyclo'. Example: gramicidin S (Moss) cyclo(-Val-Orn-Leu-D-Phe-Pro-Val-Orn-Leu-D-Phe-Pro-) cyclo(-Val-Orn-Leu-DPhe-Pro-Val-Orn-Leu-DPhe-Pro-) The sequence is again written in one line, but the residues at each end of the line are joined by a lengthened bond, e.g. (Moss)

The residues are written on two lines, so that the sequence is reversed on one of them. Hence the CO to NH direction within the peptide bond must be indicated by arrows. Hence gramicidin S may be written: (Moss)

Another example of a homodetic cyclic peptide is the cyclosporine A, which is an immunosuppressive drug:

(Chemical Book) -Usage An immunosuppressant, which has revolutionized organ transplantation through its use in the prevention of graft rejection. A group of nonpolar cyclic oligopeptides that has with immunosupppressant activity. (Chemical Book) -Reactivity Profile Cyclosporin A is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx). (Chemical Book) Heterodetic Cyclic Peptides Heterodetic cyclic peptides are peptides consisting only of amino-acid residues, but the linkages forming the ring are not solely eupeptide bonds; one or more is an isopeptide, disulfide, ester, or other bond. (Moss) Their symbolic representation follows logically from that of substituted amino acids. Examples: (Moss)

Cyclic ester of threonylglycylglycylglycine

or

. (Moss)

Other classifications for the cyclic peptides are: Depsipeptides Depsipeptides are oligomers formed from amino acids and other bifunctional acids, usually hydroxy acids. They are often cyclic. In symbolic representation, any special symbols used for the hydroxy acids should be defined. (Moss) Aureobasidin A. (AbA) is a cyclic depsipeptide antibiotic with molecular weight of 1,100 isolated from Aureobasidium pullulans R106. This product is toxic at a low concentration (0.1-0.5 g/ml) against yeast, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida glabrata. It is also effective against Aspergillus nidulans and A. niger. It is thought Aureobasidin A inhibits a yeast's enzyme, Inositol phosphorylceramide (IPC) synthase, encoding by aur1 gene, which acts in synthesis pathway of IPC. (TAKARA BIO INC)

(TAKARA BIO INC) DIDEMNIN B Activity: Anti-cancer agent via protein synthesis inhibition. (Marinebiotech.org) Early investigation into the bioactivity of this compound revealed marked antiviral and cytotoxic activity in in vitro tests using standard mouse leukemia cell lines. (Marinebiotech.org) Mechanistically, Didemnin B interrupts protein synthesis in target cells by binding noncompetitively to palmitoyl protein thioesterase. (Marinebiotech.org)

(Marinebiotech.org) Peptide Analogues Analogues of peptides in which the -CO-NH- group that joins residues is replaced by another grouping may be indicated by placing a Greek psi, followed by the replacing group in parenthesis, between the residue symbols where the change occurs. Examples: (Moss)

Bicyclic peptides

As their name indicates, are peptides which are constituted by two cycles. In resent research it has been found that they can act as potent inhibitors of histone deacetylases. (Islam, Kato, & Nishino, 2010)

Bibliografa
Chemical Book. (s.f.). Recuperado el 10 de Octubre de 2011, de Cyclosporin A: http://www.chemicalbook.com/ChemicalProductProperty_EN_CB5163816.htm David Andreu, L. R. Pptidos en biologa y biomedicina. Madrid, Espaa: RAYCAR. Islam, N. M., Kato, T., & Nishino, N. (2010). Bicyclic peptides as potent inhibitors of histone deacetylases: Optimization of alkyl loop length. Bioorganic & Medicinal Chemistry Letters (20), 997-999.

Marinebiotech.org. (s.f.). Recuperado el 10 de Octubre de 2011, de Resources: http://www.marinebiotech.org/didemninb.html Moss, G. P. (s.f.). Nomenclature and Symbolism for Amino Acids and Peptides. (Department of Chemistry, Queen Mary University of London,) Recuperado el 10 de Octubre de 2011, de http://www.chem.qmul.ac.uk/iupac/AminoAcid/A1819.html#AA195 TAKARA BIO INC. (s.f.). Recuperado el 10 de Octubre de 2011, de Genetic Engineering Research: http://catalog.takara-bio.co.jp/en/product/basic_info.asp?unitid=U100005706