Karen Anderson, PhD
Professor of Pharmacology and of Molecular Biophysics and Biochemistry; Co-Leader, Developmental Therapeutics, Yale Cancer Center; Co-Director Therapeutics/Chemotherapy Program
Research & Publications
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Research Summary
The primary emphasis focuses on developing an understanding of enzymatic reactions and receptor-ligand interactions at a molecular level. The approach is to use a combination of structural techniques including rapid transient kinetics, NMR, and xRay crystallography. This allows a quantitative and structural basis for understanding how proteins work at a molecular level.
Our ultimate goal in this research is to develop an in-depth mechanistic understanding of how enzymes function and thereby provide a more effective means of modulating their function. This approach has been used to examine a number of enzyme mechanisms including EPSP synthase, tryptophan synthase, PABA synthase, LAR-tyrosine phosphatase, and HIV reverse transcriptase. We have recently uncovered some interesting mechanistic features of HIV reverse transcriptase which may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
Specialized Terms: Enzyme function; Anti-viral agents
Extensive Research Description
Our research is directed toward understanding molecular mechanism of clinically important antimicrobial, anticancer, and antiviral molecular targets with the ultimate goal of developing more effective therapies. Key enzyme targets for the development of therapeutics include: KDO8P synthase (an important target for new antibacterials) and a bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme from parasites (a target for new antiparasitic drugs).
Also ongoing are studies to understanding the molecular mechanisms of normal and aberrant protein signaling and the effects of selectively guided anticancer drugs such as Iressa and Gleevec. Important molecular targets include EGFR, HER-2, PDGFRb, and c-kit receptor tyrosine kinases. Another area of focus involves investigating the mechanisms of HIV reverse transcriptase as well as drug resistance and toxicity that may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
Also ongoing are studies to understanding the molecular mechanisms of normal and aberrant protein signaling and the effects of selectively guided anticancer drugs such as Iressa and Gleevec. Important molecular targets include EGFR, HER-2, PDGFRb, and c-kit receptor tyrosine kinases. Another area of focus involves investigating the mechanisms of HIV reverse transcriptase as well as drug resistance and toxicity that may ultimately aid in the design of better therapeutic agents for the treatment of AIDS.
Coauthors
Research Interests
Molecular Biology; Pharmacology; Anti-Retroviral Agents; HIV Reverse Transcriptase; Multifunctional Enzymes
Selected Publications
- APOBEC as an Endogenous Mutagen in Cancers of the Head and NeckSasaki T, Issaeva N, Yarbrough W, Anderson K. APOBEC as an Endogenous Mutagen in Cancers of the Head and Neck 2018, 275-292. DOI: 10.1007/978-3-319-78762-6_10.
- Lethal Mutagenesis as an Unconventional Approach to Combat HIVIyidogan P, Anderson K. Lethal Mutagenesis as an Unconventional Approach to Combat HIV 2011, 283-306. DOI: 10.1002/9783527635955.ch11.
- 8.18 Detection of Novel Enzyme IntermediatesFurdui C, Anderson K. 8.18 Detection of Novel Enzyme Intermediates 2010, 663-688. DOI: 10.1016/b978-008045382-8.00158-1.
- The role of the proteome in catalysis and regulationAnderson K, Mattevi A. The role of the proteome in catalysis and regulation Current Opinion In Structural Biology 2004, 14: 639-641. DOI: 10.1016/j.sbi.2004.10.014.
- Catalysis and regulation: Bringing proteins to lifeAnderson K, Mattevi A. Catalysis and regulation: Bringing proteins to life Current Opinion In Structural Biology 2002, 12: 695-697. DOI: 10.1016/s0959-440x(02)00403-7.
- Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drugKRYNETSKAIA N, FENG J, KRYNETSKI E, GARCIA J, PANETTA J, ANDERSON K, EVANS W. Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug The FASEB Journal 2001, 15: 1902-1908. PMID: 11532970, DOI: 10.1096/fj.01-0124com.
- Mechanism of Action of 1-β-d-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β-d-Dioxolane GuanosineFurman P, Jeffrey J, Kiefer L, Feng J, Anderson K, Borroto-Esoda K, Hill E, Copeland W, Chu C, Sommadossi J, Liberman I, Schinazi R, Painter G. Mechanism of Action of 1-β-d-2,6-Diaminopurine Dioxolane, a Prodrug of the Human Immunodeficiency Virus Type 1 Inhibitor 1-β-d-Dioxolane Guanosine Antimicrobial Agents And Chemotherapy 2001, 45: 158-165. PMID: 11120959, PMCID: PMC90254, DOI: 10.1128/aac.45.1.158-165.2001.
- Insights into the HER-2 Receptor Tyrosine Kinase Mechanism and Substrate Specificity Using a Transient Kinetic Analysis †Jan A, Johnson E, Diamonti A, Carraway K, Anderson K. Insights into the HER-2 Receptor Tyrosine Kinase Mechanism and Substrate Specificity Using a Transient Kinetic Analysis † Biochemistry 2000, 39: 9786-9803. PMID: 10933796, DOI: 10.1021/bi9924922.
- Initiation of Minus-Strand DNA Synthesis by Human Immunodeficiency Virus Type 1 Reverse Transcriptase †Vaccaro J, Singh H, Anderson K. Initiation of Minus-Strand DNA Synthesis by Human Immunodeficiency Virus Type 1 Reverse Transcriptase † Biochemistry 1999, 38: 15978-15985. PMID: 10625465, DOI: 10.1021/bi990945x.
- Crystallographic Studies of Phosphonate-Based α-Reaction Transition-State Analogues Complexed to Tryptophan Synthase † , ‡Sachpatzidis A, Dealwis C, Lubetsky J, Liang P, Anderson K, Lolis E. Crystallographic Studies of Phosphonate-Based α-Reaction Transition-State Analogues Complexed to Tryptophan Synthase † , ‡ Biochemistry 1999, 38: 12665-12674. PMID: 10504236, DOI: 10.1021/bi9907734.
- Mechanistic studies show that (−)‐FTC‐TP is a better inhibitor of HIV‐1 reverse transcriptase than 3TC‐TPFeng J, Shi J, Schinazi R, Anderson K. Mechanistic studies show that (−)‐FTC‐TP is a better inhibitor of HIV‐1 reverse transcriptase than 3TC‐TP The FASEB Journal 1999, 13: 1511-1517. PMID: 10463941, DOI: 10.1096/fasebj.13.12.1511.
- Mechanistic Studies Examining the Efficiency and Fidelity of DNA Synthesis by the 3TC-Resistant Mutant (184V) of HIV-1 Reverse Transcriptase †Feng J, Anderson K. Mechanistic Studies Examining the Efficiency and Fidelity of DNA Synthesis by the 3TC-Resistant Mutant (184V) of HIV-1 Reverse Transcriptase † Biochemistry 1999, 38: 9440-9448. PMID: 10413520, DOI: 10.1021/bi990709m.
- Using loop length variants to dissect the folding pathway of a four-helix-bundle protein 11Edited by P. E. WrightNagi A, Anderson K, Regan L. Using loop length variants to dissect the folding pathway of a four-helix-bundle protein 11Edited by P. E. Wright Journal Of Molecular Biology 1999, 286: 257-265. PMID: 9931264, DOI: 10.1006/jmbi.1998.2474.
- [6] Fundamental mechanisms of substrate channelingAnderson K. [6] Fundamental mechanisms of substrate channeling 1999, 308: 111-145. PMID: 10507003, DOI: 10.1016/s0076-6879(99)08008-8.
- Mechanistic Studies Comparing the Incorporation of (+) and (−) Isomers of 3TCTP by HIV-1 Reverse Transcriptase †Feng J, Anderson K. Mechanistic Studies Comparing the Incorporation of (+) and (−) Isomers of 3TCTP by HIV-1 Reverse Transcriptase † Biochemistry 1998, 38: 55-63. PMID: 9890882, DOI: 10.1021/bi982340r.
- Catalytic Mechanism of Kdo8P Synthase: Transient Kinetic Studies and Evaluation of a Putative Reaction Intermediate †Liang P, Lewis J, Anderson K, Kohen A, D'Souza F, Benenson Y, Baasov T. Catalytic Mechanism of Kdo8P Synthase: Transient Kinetic Studies and Evaluation of a Putative Reaction Intermediate † Biochemistry 1998, 37: 16390-16399. PMID: 9819231, DOI: 10.1021/bi981374w.
- Implication of the tRNA Initiation Step for Human Immunodeficiency Virus Type 1 Reverse Transcriptase in the Mechanism of 3‘-Azido-3‘-deoxythymidine (AZT) Resistance †Vaccaro J, Anderson K. Implication of the tRNA Initiation Step for Human Immunodeficiency Virus Type 1 Reverse Transcriptase in the Mechanism of 3‘-Azido-3‘-deoxythymidine (AZT) Resistance † Biochemistry 1998, 37: 14189-14194. PMID: 9760256, DOI: 10.1021/bi9810353.
- Substrate Channeling and Domain−Domain Interactions in Bifunctional Thymidylate Synthase−Dihydrofolate Reductase †Liang P, Anderson K. Substrate Channeling and Domain−Domain Interactions in Bifunctional Thymidylate Synthase−Dihydrofolate Reductase † Biochemistry 1998, 37: 12195-12205. PMID: 9724533, DOI: 10.1021/bi9803168.
- Kinetic Reaction Scheme for the Dihydrofolate Reductase Domain of the Bifunctional Thymidylate Synthase−Dihydrofolate Reductase from Leishmania major †Liang P, Anderson K. Kinetic Reaction Scheme for the Dihydrofolate Reductase Domain of the Bifunctional Thymidylate Synthase−Dihydrofolate Reductase from Leishmania major † Biochemistry 1998, 37: 12206-12212. PMID: 9724534, DOI: 10.1021/bi9803170.
- Leishmania major Pteridine Reductase 1 Belongs to the Short Chain Dehydrogenase Family: Stereochemical and Kinetic Evidence †Luba J, Nare B, Liang P, Anderson K, Beverley S, Hardy L. Leishmania major Pteridine Reductase 1 Belongs to the Short Chain Dehydrogenase Family: Stereochemical and Kinetic Evidence † Biochemistry 1998, 37: 4093-4104. PMID: 9521731, DOI: 10.1021/bi972693a.
- Structure and Functional Relationships in Human pur HBeardsley G, Rayl E, Gunn K, Moroson B, Seow H, Anderson K, Vergis J, Fleming K, Worland S, Condon B, Davies J. Structure and Functional Relationships in Human pur H 1998, 431: 221-226. PMID: 9598063, DOI: 10.1007/978-1-4615-5381-6_43.
- RNA Dependent DNA Replication Fidelity of HIV-1 Reverse Transcriptase: Evidence of Discrimination between DNA and RNA Substrates †Kerr S, Anderson K. RNA Dependent DNA Replication Fidelity of HIV-1 Reverse Transcriptase: Evidence of Discrimination between DNA and RNA Substrates † Biochemistry 1997, 36: 14056-14063. PMID: 9369477, DOI: 10.1021/bi971385+.
- Pre-Steady-State Kinetic Characterization of Wild Type and 3‘-Azido-3‘-deoxythymidine (AZT) Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Implication of RNA Directed DNA Polymerization in the Mechanism of AZT Resistance †Kerr S, Anderson K. Pre-Steady-State Kinetic Characterization of Wild Type and 3‘-Azido-3‘-deoxythymidine (AZT) Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Implication of RNA Directed DNA Polymerization in the Mechanism of AZT Resistance † Biochemistry 1997, 36: 14064-14070. PMID: 9369478, DOI: 10.1021/bi9713862.
- Catalytic mechanism of KDO8P synthase. Pre-steady-state kinetic analysis using rapid chemical quench flow methodsLiang P, Kohen A, Baasov T, Anderson K. Catalytic mechanism of KDO8P synthase. Pre-steady-state kinetic analysis using rapid chemical quench flow methods Bioorganic & Medicinal Chemistry Letters 1997, 7: 2463-2468. DOI: 10.1016/s0960-894x(97)10021-x.
- Pre-Steady-State Kinetic Analysis of the Trichodiene Synthase Reaction Pathway †Cane D, Chiu H, Liang P, Anderson K. Pre-Steady-State Kinetic Analysis of the Trichodiene Synthase Reaction Pathway † Biochemistry 1997, 36: 8332-8339. PMID: 9204880, DOI: 10.1021/bi963018o.
- Surface point mutations that significantly alter the structure and stability of a protein's denatured stateSmith C, Bu Z, Engelman D, Regan L, Anderson K, Sturtevant J. Surface point mutations that significantly alter the structure and stability of a protein's denatured state Protein Science 1996, 5: 2009-2019. PMID: 8897601, PMCID: PMC2143264, DOI: 10.1002/pro.5560051007.
- Kinetic Characterization of Channel Impaired Mutants of Tryptophan Synthase (∗)Anderson K, Kim A, Quillen J, Sayers E, Yang X, Miles E. Kinetic Characterization of Channel Impaired Mutants of Tryptophan Synthase (∗) Journal Of Biological Chemistry 1995, 270: 29936-29944. PMID: 8530393, DOI: 10.1074/jbc.270.50.29936.
- Expression of Human Cyclophilin‐40 and the Effect of the His141→Trp Mutation on Catalysis and Cyclosporin A BindingHoffmann K, Kakalis L, Anderson K, Armitage I, Handschumacher R. Expression of Human Cyclophilin‐40 and the Effect of the His141→Trp Mutation on Catalysis and Cyclosporin A Binding The FEBS Journal 1995, 229: 188-193. PMID: 7744028, DOI: 10.1111/j.1432-1033.1995.0188l.x.