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antibody catalyzes Diels-Alder
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Author Topic: antibody catalyzes Diels-Alder
dm_telvis
unregistered posted 06-11-98 09:00 AM
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here is the url for abstracts of articles
http://x13.dejanews.com/getdoc.xp?AN=361636380.1&search=thread&threaded=1&CONTEXT=897571952.390529111&HIT_CONTEXT=897571884.387449015&HIT_NUM=7&hitnum=5
relating to an incredible use of immune system protein complexes to catalyze organic reactions! i can't wait to see the actual article! this is exactly what i meant by using custom proteins...this is the future, the cutting edge of synthetic technology.
comments? dm_telvis@yahoo.com
dm_telvis
unregistered posted 06-11-98 09:37 AM
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here it is ...
n article <6lm5gn$gc5$1@nnrp1.dejanews.com> , dm_telvis@yahoo.com writes:
>if this is true, post that reference right here!
Here's an incomplete list (though it gets the hottest ones, I think, and
gives a bonus at the end 
)
Science 1998 Mar 20;279(5358):1934-1940
An antibody exo Diels-Alderase inhibitor complex at 1.95 angstrom
resolution.
Heine A, Stura EA, Yli-Kauhaluoma JT, Gao C, Deng Q, Beno BR, Houk KN,
Janda KD, Wilson IA
The Skaggs Institute of Chemical Biology, Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
A highly specific Diels-Alder protein catalyst was made by manipulating
the antibody repertoire of the immune system. The catalytic antibody 13G5
catalyzes a disfavored exo Diels-Alder transformation in a reaction for
which there is no natural enzyme counterpart and that yields a single
regioisomer in high enantiomeric excess. The crystal structure of the
antibody Fab in complex with a ferrocenyl inhibitor containing the
essential haptenic core that elicited 13G5 was determined at 1.95
angstrom resolution. Three key antibody residues appear to be responsible
for the observed catalysis and product control. Tyrosine-L36 acts as a
Lewis acid activating the dienophile for nucleophilic attack, and
asparagine-L91 and aspartic acid-H50 form hydrogen bonds to the
carboxylate side chain that substitutes for the carbamate diene
substrate. This hydrogen-bonding scheme leads to rate acceleration and
also pronounced stereoselectivity. Docking experiments with the four
possible ortho transition states of the reaction explain the specific exo
effect and suggest that the (3R,4R)-exo stereoisomer is the preferred
product.
PMID: 9506943, UI: 98176010
Science 1998 Mar 20;279(5358):1929-1933
Immunological origins of binding and catalysis in a Diels-Alderase
antibody.
Romesberg FE, Spiller B, Schultz PG, Stevens RC
Howard Hughes Medical Institute and the Department of Chemistry,
University of California, Berkeley, CA 94720, USA. 94720, USA.
The three-dimensional structure of an antibody (39-A11) that catalyzes a
Diels-Alder reaction has been determined. The structure suggests that the
antibody catalyzes this pericyclic reaction through a combination of
packing and hydrogen-bonding interactions that control the relative
geometries of the bound substrates and electronic distribution in the
dienophile. A single somatic mutation, serine-91 of the light chain to
valine, is largely responsible for the increase in affinity and catalytic
activity of the affinity-matured antibody. Structural and functional
studies of the germ-line precursor suggest that 39-A11 and related
antibodies derive from a family of germ-line genes that have been
selected throughout evolution for the ability of the encoded proteins to
form a polyspecific combining site. Germ line-encoded antibodies of this
type, which can rapidly evolve into high-affinity receptors for a broad
range of structures, may help to expand the binding potential associated
with the structural diversity of the primary antibody repertoire.
PMID: 9506942, UI: 98176009
Bioorg Med Chem 1996 Jul;4(7):1051-1057
Regioselectivity and enantioselectivity in an antibody catalyzed hetero
Diels-Alder reaction.
Meekel AA, Resmini M, Pandit UK
Laboratory of Organic Chemistry, University of Amsterdam, The
Netherlands.
The Diels-Alder cycloadditions of trans- and cis-piperylene (1 and 2) to
4-nitroso-N-propylbenzamide (3) were selected as target reactions for the
development of catalytic antibodies with regioselective and
enantioselective properties (Meekel, A. A. P. Ph.D. Thesis, University of
Amsterdam, 1995). The bicyclic systems 10a-c were designed as transition
state analogues and employed for the immunization of mice and the
generation of monoclonal antibodies. Three of the antibodies, each
obtained from immunization with a different hapten, were selected for
further characterization of their catalytic activities. Among these,
antibody 309-1G7, raised against the protein conjugate of 10c, showed the
best rate enhancement (kcat/ kuncat = 2618) in the reaction of
cis-piperylene (2) with nitroso dienophile 3. Data obtained from
regioselectivity and enantioselectivity analyses demonstrated that
antibody 309-1G7 favors the formation of the targeted regioisomer (>
95%), with an ee of 82%.
PMID: 8831976, UI: 96428874
Science 1993 Oct 8;262(5131):204-208
Control of the exo and endo pathways of the Diels-Alder reaction by
antibody catalysis.
Gouverneur VE, Houk KN, de Pascual-Teresa B, Beno B, Janda KD, Lerner RA
Department of Molecular Biology, Scripps Research Institute, La Jolla, CA
92037.
Catalytic antibodies that control the reaction pathways of the
Diels-Alder cycloaddition have been generated. One antibody catalyzes the
favored endo and the other the disfavored exo pathway to yield the
respective cis and trans adducts in enantiomerically pure form. A
comparison of the x-ray structure of the hapten with the calculated
geometry of the transition structure showed that [2.2.2] bicyclic
compounds are excellent mimics of the transition state of the Diels-Alder
reaction. To achieve catalysis and the high degree of stereoselectivity
shown here, the antibody must simultaneously control the conformation of
the individual reactants and their relation to each other. In the case of
the disfavored process, binding energy must be used to reroute the
reaction along a higher energy pathway. The rerouting of reaction
pathways has become a major focus of antibody catalysis and other
disfavored reactions can be expected to be catalyzed so long as the
energy barrier is not extreme. The energy requirements needed for
absolute control of all of the stereoisomers of many Diels-Alder
reactions fall in the energy range (approximately 20 kilocalories per
mole) deliverable by antibody binding.
PMID: 8211138, UI: 94023957
Experientia 1991 Dec 1;47(11-12):1139-1148
Molecular recognition in applied enzyme chemistry.
Suckling CJ
Department of Pure and Applied Chemistry, University of Strathclyde,
Glasgow, Scotland.
Molecular recognition impinges upon many fields of biological chemistry,
especially those involving catalytic processes. This review gives
examples from studies at Strathclyde of both small and macromolecular
systems. Mechanism-based enzyme inhibitors are described with reference
to dihydrofolate reductase, dihydroorotate dehydrogenase, and cholesterol
metabolism. Applications of molecular recognition related to synthetic
transformations are discussed in terms of aromatic substitution,
chemically modified papain, and catalytic antibodies for Diels-Alder
reactions.
PMID: 1765126, UI: 92111689
Nature 1997 Sep 4;389(6646):54-57
RNA-catalysed carbon-carbon bond formation.
Tarasow TM, Tarasow SL, Eaton BE
NeXstar Pharmaceuticals, Inc., Boulder, Colorado 80301, USA.
The 'RNA world' hypothesis, which assumes that the chemical processes
that led to the appearance of life were carried out by RNA molecules, has
stimulated interest in catalytic reactions involving oligonucleotides
such as catalytic RNA (ribozymes). Naturally occurring ribozymes have,
for example, been shown to efficiently catalyse the formation and
cleavage of nucleic-acid phosphodiester bonds, and this narrow range of
RNA-catalysed reactions has been subsequently expanded by in vitro
selection methods to include ester and amide bond formation S(N)2
reactions and porphyrin metallations. Carbon-carbon bond formation and
the creation of asymmetric centres are both of great importance
biochemically, but have not yet been accomplished by RNA catalysis. A
Junior Member posted
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