John F. Andersen

National Institute of Allergy and Infectious Diseases

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José M. C. Ribeiro

Vector Oncology (United States)

Ivo M.B. Francischetti

Johns Hopkins University

Jesús G. Valenzuela

Vector Oncology (United States)

Michail Kotsyfakis

Czech Academy of Sciences, Biology Centre

Eric Calvo

National Institute of Allergy and Infectious Diseases

Van My Pham

Vector Oncology (United States)

W.R. Montfort

University of Arizona

Ben J. Mans

Onderstepoort Veterinary Institute

A. Weichsel

University of Arizona

Patrícia H. Alvarenga

National Institute of Allergy and Infectious Diseases

Cooperative Institutions

National Institutes of Health

179

National Institute of Allergy and Infectious Diseases

167

Vector (United States)

Vector Oncology (United States)

Universidade Federal do Rio de Janeiro

University of Arizona

Government of the United States of America

National Cancer Institute

Instituto Nacional de Ciência e Tecnologia em Entomologia Molecular

Johns Hopkins University

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Kinetics and Equilibria in Ligand Binding by Nitrophorins 1−4: Evidence for Stabilization of a Nitric Oxide−Ferriheme Complex through a Ligand-Induced Conformational Trap

Biochemistry (2000)

John F. Andersen Xiao Dong Ding Celia A. Balfour Tatjana Kh. Shokhireva Donald E. Champagne

Nitrophorins 1−4 (NP1−4) are ferriheme proteins from the blood-sucking insect Rhodnius prolixus that transport nitric oxide (NO) to the victim, sequester histamine, and inhibit blood coagulation. Here, we report kinetic and thermodynamic analyses for ligand binding by all four proteins and their reduction potentials. All four undergo biphasic association and dissociation reactions with NO. The initial association is fast (1.5−33 μM-1 s-1) and similar to that of elephant metmyoglobin. However, unlike in metmyoglobin, a slower second phase follows (∼50 s-1), and the stabilized final complexes are resistant to autoreduction (E° = +3 to +154 mV vs normal hydrogen electrode). NO dissociation begins with a slow, pH-dependent step (0.02−1.4 s-1), followed by a faster phase that is again similar to that of metmyoglobin (3−52 s-1). The equilibrium dissociation constants are quite small (1−850 nM). NP1 and NP4 display larger release rate constants and smaller association rate constants than NP2 and NP3, leading to values for Kd that are about 10-fold greater. The results are discussed in light of the recent crystal structures of NP1, NP2, and NP4, which display open, polar distal pockets, and of NP4−NO, which displays an NO-induced conformational change that leads to expulsion of solvent and complete burial of the NO ligand in a now nonpolar distal pocket. Taken together, the results suggest that tighter NO binding in the nitrophorins is due to the trapping of the molecule in a nonpolar distal pocket rather than through formation of particularly strong Fe−NO or hydrogen bonds.

Metmyoglobin

Conformational change

10.1021/bi000766b

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Citations (120)

Structure and Function of a “Yellow” Protein from Saliva of the Sand Fly Lutzomyia longipalpis That Confers Protective Immunity against Leishmania major Infection

Journal of Biological Chemistry (2011)

Xueqing Xu Fabiano Oliveira Bianca W. Chang Nicolas Collin Régis Gomes

LJM11, an abundant salivary protein from the sand fly Lutzomyia longipalpis, belongs to the insect "yellow" family of proteins. In this study, we immunized mice with 17 plasmids encoding L. longiplapis salivary proteins and demonstrated that LJM11 confers protective immunity against Leishmania major infection. This protection correlates with a strong induction of a delayed type hypersensitivity (DTH) response following exposure to L. longipalpis saliva. Additionally, splenocytes of exposed mice produce IFN-γ upon stimulation with LJM11, demonstrating the systemic induction of Th1 immunity by this protein. In contrast to LJM11, LJM111, another yellow protein from L. longipalpis saliva, does not produce a DTH response in these mice, suggesting that structural or functional features specific to LJM11 are important for the induction of a robust DTH response. To examine these features, we used calorimetric analysis to probe a possible ligand binding function for the salivary yellow proteins. LJM11, LJM111, and LJM17 all acted as high affinity binders of prohemostatic and proinflammatory biogenic amines, particularly serotonin, catecholamines, and histamine. We also determined the crystal structure of LJM11, revealing a six-bladed β-propeller fold with a single ligand binding pocket located in the central part of the propeller structure on one face of the molecule. A hypothetical model of LJM11 suggests a positive electrostatic potential on the face containing entry to the ligand binding pocket, whereas LJM111 is negative to neutral over its entire surface. This may be the reason for differences in antigenicity between the two proteins.

Antigenicity

10.1074/jbc.m111.268904

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TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein

Science (2005)

Felix Yarovinsky Dekai Zhang John F. Andersen Gerard Bannenberg Charles N. Serhan

Mammalian Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs). Although TLRs are clearly involved in the detection of bacteria and viruses, relatively little is known about their function in the innate response to eukaryotic microorganisms. Here we identify a profilin-like molecule from the protozoan parasite Toxoplasma gondii that generates a potent interleukin-12 (IL-12) response in murine DCs that is dependent on myeloid differentiation factor 88. T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced IL-12 production and optimal resistance to infection, thereby establishing a role for the receptor in host recognition of protozoan pathogens.

Profilin

Protozoan parasite

10.1126/science.1109893

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Citations (1,008)

Photoaffinity labeling of methyl farnesoate epoxidase in cockroach corpora allata

Insect Biochemistry and Molecular Biology (1995)

John F. Andersen Marco Ceruso Gopalan C. Unnithan Eiichi Kuwano Glenn D. Prestwich

Corpus allatum

Photoaffinity labeling

Diazirine

10.1016/0965-1748(95)00010-s

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Citations (14)

Inhibition of tissue factor by ixolaris reduces primary tumor growth and experimental metastasis in a murine model of melanoma

Thrombosis Research (2012)

Andreia D. S. Oliveira Luize Goncalves Lima A. Mariano-Oliveira Daniel Escorsim Machado Luiz Eurico Nasciutti

Primary tumor

10.1016/j.thromres.2012.05.021

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Citations (32)

A bispecific inhibitor of complement and coagulation blocks activation in complementopathy models via a novel mechanism

Blood (2023)

John F. Andersen Haotian Lei Ethan C. Strayer Tapan Kanai Van Pham

C3-convertase

C1-inhibitor

10.1182/blood.2022019359

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Citations (6)

Structure and Ligand-Binding Mechanism of a Cysteinyl Leukotriene-Binding Protein from a Blood-Feeding Disease Vector

ACS Chemical Biology (2016)

Willy Jablonka Van My Pham Glenn Nardone Apostolos G. Gittis Lívia Silva-Cardoso

Blood-feeding disease vectors mitigate the negative effects of hemostasis and inflammation through the binding of small-molecule agonists of these processes by salivary proteins. In this study, a lipocalin protein family member (LTBP1) from the saliva of Rhodnius prolixus, a vector of the pathogen Trypanosoma cruzi, is shown to sequester cysteinyl leukotrienes during feeding to inhibit immediate inflammatory responses. Calorimetric binding experiments showed that LTBP1 binds leukotrienes C4 (LTC4), D4 (LTD4), and E4 (LTE4) but not biogenic amines, adenosine diphosphate, or other eicosanoid compounds. Crystal structures of ligand-free LTBP1 and its complexes with LTC4 and LTD4 reveal a conformational change during binding that brings Tyr114 into close contact with the ligand. LTC4 is cleaved in the complex, leaving free glutathione and a C20 fatty acid. Chromatographic analysis of bound ligands showed only intact LTC4, suggesting that cleavage could be radiation-mediated.

Eicosanoid metabolism

Leukotriene E4

Leukotriene C4

10.1021/acschembio.6b00032

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Citations (10)

A unique, highly conserved secretory invertase is differentially expressed by promastigote developmental forms of all species of the human pathogen, Leishmania

Molecular and Cellular Biochemistry (2015)

Todd A. Lyda Manju B. Joshi John F. Andersen Andrew Y. Kelada Joshua P. Owings

Amastigote

10.1007/s11010-015-2366-6

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Citations (13)

Salivary Antigen-5/CAP Family Members Are Cu2+-dependent Antioxidant Enzymes That Scavenge O2⨪ and Inhibit Collagen-induced Platelet Aggregation and Neutrophil Oxidative Burst

Journal of Biological Chemistry (2013)

Teresa C. F. Assumpção Dongying Ma Alexandra Schwarz Karine Reiter Jaime M. Santana

The function of the antigen-5/CAP family of proteins found in the salivary gland of bloodsucking animals has remained elusive for decades. Antigen-5 members from the hematophagous insects Dipetalogaster maxima (DMAV) and Triatoma infestans (TIAV) were expressed and discovered to attenuate platelet aggregation, ATP secretion, and thromboxane A2 generation by low doses of collagen (<1 μg/ml) but no other agonists. DMAV did not interact with collagen, glycoprotein VI, or integrin α2β1. This inhibitory profile resembles the effects of antioxidants Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in platelet function. Accordingly, DMAV was found to inhibit cytochrome c reduction by O2⨪ generated by the xanthine/xanthine oxidase, implying that it exhibits antioxidant activity. Moreover, our results demonstrate that DMAV blunts the luminescence signal of O2⨪ generated by phorbol 12-myristate 13-acetate-stimulated neutrophils. Mechanistically, inductively coupled plasma mass spectrometry and fluorescence spectroscopy revealed that DMAV, like Cu,Zn-SOD, interacts with Cu2+, which provides redox potential for catalytic removal of O2⨪. Notably, surface plasmon resonance experiments (BIAcore) determined that DMAV binds sulfated glycosaminoglycans (e.g. heparin, KD ∼100 nmol/liter), as reported for extracellular SOD. Finally, fractions of the salivary gland of D. maxima with native DMAV contain Cu2+ and display metal-dependent antioxidant properties. Antigen-5/CAP emerges as novel family of Cu2+-dependent antioxidant enzymes that inhibit neutrophil oxidative burst and negatively modulate platelet aggregation by a unique salivary mechanism. The function of the antigen-5/CAP family of proteins found in the salivary gland of bloodsucking animals has remained elusive for decades. Antigen-5 members from the hematophagous insects Dipetalogaster maxima (DMAV) and Triatoma infestans (TIAV) were expressed and discovered to attenuate platelet aggregation, ATP secretion, and thromboxane A2 generation by low doses of collagen (<1 μg/ml) but no other agonists. DMAV did not interact with collagen, glycoprotein VI, or integrin α2β1. This inhibitory profile resembles the effects of antioxidants Cu,Zn-superoxide dismutase (Cu,Zn-SOD) in platelet function. Accordingly, DMAV was found to inhibit cytochrome c reduction by O2⨪ generated by the xanthine/xanthine oxidase, implying that it exhibits antioxidant activity. Moreover, our results demonstrate that DMAV blunts the luminescence signal of O2⨪ generated by phorbol 12-myristate 13-acetate-stimulated neutrophils. Mechanistically, inductively coupled plasma mass spectrometry and fluorescence spectroscopy revealed that DMAV, like Cu,Zn-SOD, interacts with Cu2+, which provides redox potential for catalytic removal of O2⨪. Notably, surface plasmon resonance experiments (BIAcore) determined that DMAV binds sulfated glycosaminoglycans (e.g. heparin, KD ∼100 nmol/liter), as reported for extracellular SOD. Finally, fractions of the salivary gland of D. maxima with native DMAV contain Cu2+ and display metal-dependent antioxidant properties. Antigen-5/CAP emerges as novel family of Cu2+-dependent antioxidant enzymes that inhibit neutrophil oxidative burst and negatively modulate platelet aggregation by a unique salivary mechanism.

10.1074/jbc.m113.466995

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Citations (67)

Characterization of Saccharopolyspora erythraea cytochrome P-450 genes and enzymes, including 6-deoxyerythronolide B hydroxylase

Journal of Bacteriology (1992)

John F. Andersen C. Richard Hutchinson

Previous studies of erythromycin biosynthesis have indicated that a cytochrome P-450 monooxygenase system is responsible for hydroxylation of 6-deoxyerythronolide B to erythronolide B as part of erythromycin biosynthesis in Saccharopolyspora erythraea (A. Shafiee and C. R. Hutchinson, Biochemistry 26:6204-6210 1987). The enzyme was previously purified to apparent homogeneity and found to have a catalytic turnover number of approximately 10(-3) min-1. More recently, disruption of a P-450-encoding sequence (eryF) in the region of ermE, the erythromycin resistance gene of S. erythraea, produced a 6-deoxyerythronolide B hydroxylation-deficient mutant (J. M. Weber, J. O. Leung, S. J. Swanson, K. B. Idler, and J. B. McAlpine, Science 252:114-116, 1991). In this study we purified the catalytically active cytochrome P-450 fraction from S. erythraea and found by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis that it consists of a major and a minor P-450 species. The gene encoding the major species (orf405) was cloned from genomic DNA and found to be distinct from eryF. Both the orf405 and eryF genes were expressed in Escherichia coli, and the properties of the proteins were compared. Heterologously expressed EryF and Orf405 both reacted with antisera prepared against the 6-deoxyerythronolide B hydroxylase described by Shafiee and Hutchinson (1987), and the EryF polypeptide comigrated with the minor P-450 species from S. erythraea on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels. In comparisons of enzymatic activity, EryF hydroxylated a substrate with a turnover number of 53 min-1, whereas Orf405 showed no detectable activity with a 6-deoxyerythronolide B analog. Both enzymes showed weak activity in the O-dealkylation of 7-ethoxycoumarin. We conclude that the previously isolated 6-deoxyerythronolide B hydroxylase was a mixture of two P-450 enzymes and that only the minor form shows 6-deoxyerythronolide B hydroxylase activity.

Hydroxylation

10.1128/jb.174.3.725-735.1992

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Citations (87)