Selective Chemical Catalysis by an Antibody

Pollack, Scott J.; Jacobs, J. W.; Schultz, Peter G.

doi:10.1126/science.3787262

Cited by 622 publications

(233 citation statements)

References 27 publications

Supporting

Mentioning

220

Contrasting

Unclassified

Order By: Relevance

“…For most part of antibodies, this observation is correct. At the same time during the last 30 years, it was shown that Abs against chemically stable analogues modeling the transition states of chemical reaction can catalyze many different reactions [1][2][3][4][5][6][7][8]. Such artificial catalytic antibodies were called abzymes (derived from antibody enzymes).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Nevinsky¹

2017

Lupus

321

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is known as a systemic polyethiologic diffuse autoimmune disease characterized by connective tissue disorganization and the paramount damage of skin and visceral capillaries. Usually, SLE symptoms include high fever, hair loss, mouth ulcers, chest pain, swollen lymph nodes, painful and swollen joints, increased fatigue, and appearance of red rash more often on the face. The exact reason of SLE appearance is not really clear. Detection of catalytic Abs (abzymes) was shown to be the earliest indicator of different AI disease development. Some abzymes are cytotoxic and can play a dangerous negative role in the pathogenesis of AI diseases. SLE is characterized by the appearance of abzymes with several different catalytic functions including hydrolysis of peptides and proteins, DNA, RNA, and oligosaccharides. In addition, monoclonal SLE abzymes are characterized by extraordinary diversity in the affinity to the substrates, physicochemical and catalytic characteristics, optimal conditions of catalysis, cytotoxicity, etc. Production of abzymes in SLE mice is associated with changes in the differentiation of hematopoietic stem cells of bone marrow, increase in lymphocyte proliferation, and significant suppression of cell apoptosis in different organs. In this chapter, abzymes with different catalytic activities in SLE are described.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Such artificial catalytic antibodies were called abzymes (derived from antibody enzymes). Abzymes (Abzs) can catalyze more than 200 different chemical reactions and are new biological catalysts attracting great interest during recent years and are well described (for review see [1][2][3][4][5][6][7][8] and refs therein).…”

Section: Introductionmentioning

confidence: 99%

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Nevinsky¹

2017

Lupus

321

View full text Add to dashboard Cite

show abstract

“…However, although it is possible in principle to modify the active site of any native enzyme to generate nonnatural activity, this approach has met with only limited success because of the difficulties involved in predicting the effect of sequence modifications on structure and function. Catalytic antibodies based on the properties of the immune system in generating binding sites that are complementary to transition-state analogues have been shown to be efficient catalysts for numerous chemical reactions (15)(16). Their catalytic efficiencies, based mainly on transition-state stabilization, have been shown to be comparable with those at the lower end of naturally occurring enzymes, and they may improve further as our understanding of how to design transition-state analogues develops (17).…”

mentioning

confidence: 99%

Incorporation of a single His residue by rational design enables thiol-ester hydrolysis by human glutathione transferase A1-1

Hederos

Broo²,

Jakobsson³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A strategy for rational enzyme design is reported and illustrated by the engineering of a protein catalyst for thiol-ester hydrolysis. Five mutants of human glutathione (GSH; ␥-Glu-Cys-Gly) transferase A1-1 were designed in the search for a catalyst and to provide a set of proteins from which the reaction mechanism could be elucidated. The single mutant A216H catalyzed the hydrolysis of the S-benzoyl ester of GSH under turnover conditions with a kcat͞KM of 156 M ؊1 ⅐min ؊1 , and a catalytic proficiency of >10 7 M ؊1 when compared with the first-order rate constant of the uncatalyzed reaction. The wild-type enzyme did not hydrolyze the substrate, and thus, the introduction of a single histidine residue transformed the wild-type enzyme into a turnover system for thiol-ester hydrolysis. By kinetic analysis of single, double, and triple mutants, as well as from studies of reaction products, it was established that the enzyme A216H catalyzes the hydrolysis of the thiol-ester substrate by a mechanism that includes an acyl intermediate at the side chain of Y9. Kinetic measurements and the crystal structure of the A216H GSH complex provided compelling evidence that H216 acts as a general-base catalyst. The introduction of a single His residue into human GSH transferase A1-1 created an unprecedented enzymatic function, suggesting a strategy that may be of broad applicability in the design of new enzymes. The protein catalyst has the hallmarks of a native enzyme and is expected to catalyze various hydrolytic, as well as transesterification, reactions.T he quest for new enzymes extends the boundaries of our understanding of catalysis and protein structure and is expected, when successful, to generate new biocatalysts for reactions that are not catalyzed by nature (1-3). It allows for unprecedented opportunities in chemistry, but the implementation of nonnative catalytic functions in protein scaffolds remains a challenge. The redesign of protein macromolecules provides a powerful strategy for engineering nonnatural reactive sites and determining structure-function relationships. For example, the functional swapping between native enzymes has been instructive (4-8), and new catalytic activities have been introduced by chemical modification of amino acid side chains (9). In addition, the incorporation of amino acid residues in the active sites of native enzymes has been used to alter the fate of the natural substrates or inhibitors (10-14). However, although it is possible in principle to modify the active site of any native enzyme to generate nonnatural activity, this approach has met with only limited success because of the difficulties involved in predicting the effect of sequence modifications on structure and function. Catalytic antibodies based on the properties of the immune system in generating binding sites that are complementary to transition-state analogues have been shown to be efficient catalysts for numerous chemical reactions (15)(16). Their catalytic efficiencies, based mainly on transition-state stabilization...

show abstract

“…Phosphonate derivatives were the first and most successful haptens to elicit tailor-made esterolytic catAbs. They show good approximation of the transition state of substrates for ester hydrolysis because of their tetrahedral geometry and anionic character (3,4). Since then, a variety of catAbs has been generated based on haptenic TSAs (5).…”

mentioning

confidence: 99%

Molecular Evolution of Catalytic Antibodies in Autoimmune Mice

Sun

Takahashi

Kakinuma

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Catalytic Abs (catAbs) preferentially evolved in autoimmune MRL/MPJ-lpr/lpr (MRL/lpr) mice upon immunization with the phosphonate transition-state analogue (TSA), but this did not happen in normal BALB/c mice. The majority of the catAbs from MRL/lpr mice were from several independent clones of the same family. Most of them had a lysine at position 95 in the heavy chain (H95), which is at the junctional region. This residue, which interacts with the phosphonate moiety of the TSA and presumably is involved in the catalytic activity, was not changed even after expansive evolution following multiple mutations. By contrast, the majority that arose from BALB/c mice were the non-catAbs, which were quite different in the sequence from the catAbs from MRL/lpr mice, but they were clonally related to one another, so most of them were originated from a single clone. In the MRL/lpr mice, the catalytic subsets that existed in the initial repertoire were effectively captured by the phosphonyl oxygens in the TSA by interacting with the lysine at H95. In the BALB/c mice, however, another noncatalytic subset with only the binding capability directed to a moiety other than the phosphonate moiety was alternatively evolved, because of the lowest abundance or elimination of the catalytic subsets.

show abstract

Selective Chemical Catalysis by an Antibody

Cited by 622 publications

References 27 publications

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

Incorporation of a single His residue by rational design enables thiol-ester hydrolysis by human glutathione transferase A1-1

Molecular Evolution of Catalytic Antibodies in Autoimmune Mice

Contact Info

Product

Resources

About