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Biomedical subjects

A Achari

Publications and source records attributed to A Achari.

16 recordsLinked to original sources
PubMed2001

Anteroapical stunning and left ventricular outflow tract obstruction.

Dynamic left ventricular outflow tract (LVOT) obstruction is typically observed in the setting of hypertrophic cardiomyopathy. It has also been reported with concentric LV hypertrophy, excessive sympathetic stimulation, and acute myocardial infarction. We describe 3 patients with chest discomfort after emotional stress, who had pronounced abnormalities on electrocardiograms, insignificant obstructive coronary disease and hemodynamic instability with LVOT obstruction, and regional wall motion abnormalities. Suppression of contractility with beta-blockers resulted in resolution of the gradient and in clinical improvement. On follow-up, functional recovery was excellent, and ventricular function had normalized. The conditions and mechanisms that may produce this sequence of events are discussed. The most probable scenario is that an acute ischemic insult secondary to vasospasm, LV stunning, and acute geometric remodeling produced a substrate for LVOT obstruction that was exacerbated by basal LV hypercontractility. The importance of this observation is that routine treatment of cardiogenic shock cannot be used and that conservative management results in excellent prognosis.

Aged↗
PubMed1999

2.0 A X-ray structure of the ternary complex of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase from Escherichia coli with ATP and a substrate analogue.

The X-ray crystal structure of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase (PPPK) in a ternary complex with ATP and a pterin analogue has been solved to 2.0 A resolution, giving, for the first time, detailed information of the PPPK/ATP intermolecular interactions and the accompanying conformational change. The first 100 residues of the 158 residue peptide contain a betaalpha betabeta alphabeta motif present in several other proteins including nucleoside diphosphate kinase. Comparative sequence examination of a wide range of prokaryotic and lower eukaryotic species confirms the conservation of the PPPK active site, indicating the value of this de novo folate biosynthesis pathway enzyme as a potential target for the development of novel broad-spectrum anti-infective agents.

Adenosine Triphosphate↗
PubMed1998

A novel method for endoluminal treatment of abdominal aortic aneurysms. With bare-metal Wallstent endoprostheses and endovascular coils.

The established therapy for symptomatic, expanding abdominal aortic aneurysms is open surgical replacement with an artificial graft. Over the last several years, there has been increasing enthusiasm for the use of endoluminal graft prostheses to exclude abdominal aortic aneurysms. However, even with rapid advances in stent graft technology, certain problems (i.e., large profile of the devices, risk of thromboembolism, poor flexibility, endoleak formation, and side-branch occlusion) have yet to be overcome. We present the case of an 85-year-old woman with multiple comorbid illnesses who underwent endoluminal repair of her expanding abdominal aortic aneurysms. We used bare-metal Wallstent endoprostheses (Schneider, Inc.; Minneapolis, Minn) in combination with endovascular coils (Cook, Inc.; Bloomington, Ind). The bare-metal Wallstent endoprostheses were used because the patient had severely narrowed iliac arteries and a large side branch originating from the aneurysm. The procedure was technically successful, and there was no significant morbidity. Follow-up angiographic evaluation at 6 months revealed no evidence of vascular enlargement; it also revealed preservation of important side branches, and spontaneous thrombosis of the aneurysms.

Aged↗
PubMed1997

Crystal structure of the anti-bacterial sulfonamide drug target dihydropteroate synthase.

Sulfonamides were amongst the first clinically useful antibacterial agents to be discovered. The identification of sulfanilamide as the active component of the dye Prontosil rubrum led to the synthesis of clinically useful analogues. Today sulfamethoxazole (in combination with trimethoprim), is used to treat urinary tract infections caused by bacteria such as Escherichia coli and is also a first-line treatment for pneumonia caused by the fungus Pneumocystis carinii, a common condition in AIDS patients. The site of action is the de novo folate biosynthesis enzyme dihydropteroate synthase (DHPS) where sulfonamides act as analogues of one of the substrates, para-aminobenzoic acid (pABA). We report here the crystal structure of E.coli DHPS at 2.0 A resolution refined to an R-factor of 0.185. The single domain of 282 residues forms an eight-stranded alpha/beta-barrel. The 7,8-dihydropterin pyrophosphate (DHPPP) substrate binds in a deep cleft in the barrel, whilst sulfanilamide binds closer to the surface. The DHPPP ligand site is highly conserved amongst prokaryotic and eukaryotic DHPSs.

Amino Acid Sequence↗
PubMed1996

Acute varicella hepatitis in human T-cell lymphotrophic virus types I and II infection.

Varicella (chicken pox) is a common viral infection in children and generally runs a benign course. However, in adults, and especially in immunocompromised subjects such as those on immunosuppressant therapy or with AIDS, varicella infection is particularly severe and is associated with the formation of hemorrhagic skin lesions and visceral involvement. These patients are at an increased risk of developing varicella hepatitis, which frequently results in fulminant hepatic failure and death. In the present report, we describe for the first time the course of disease and the histological appearance of varicella hepatitis in a patient infected with the human T cell lymphotropic viruses (HTLV) I and II; these viruses have many characteristics in common with the human immunodeficiency virus (HIV). Our patient had a relatively benign illness, suggesting that varicella infection in the presence of HTLVI and II may not run as severe a course as it does in patients with HIV infection.

Acyclovir↗
PubMed1994

The structure of Pneumocystis carinii dihydrofolate reductase to 1.9 A resolution.

BACKGROUND: The fungal pathogen Pneumocystis carinii causes a pneumonia which is an opportunistic infection of AIDS patients. Current therapy includes the dihydrofolate reductase (DHFR) inhibitor trimethoprim which is selective but only a relatively weak inhibitor of the enzyme for P. carinii. Determination of the three-dimensional structure of the enzyme should form the basis for design of more potent and selective therapeutic agents for treatment of the disease. RESULTS: The structure of P. carinii DHFR in complex with reduced nicotinamide adenine dinucleotide phosphate and trimethoprim has accordingly been solved by X-ray crystallography. The structure of the ternary complex has been refined at 1.86 A resolution (R = 0.181). A similar ternary complex with piritrexim (which is a tighter binding, but less selective inhibitor) has also been solved, as has the binary complex holoenzyme, both at 2.5 A resolution. CONCLUSIONS: These structures show how two drugs interact with a fungal DHFR. A comparison of the three-dimensional structure of this relatively large DHFR with bacterial or mammalian enzyme-inhibitor complexes determined previously highlights some additional secondary structure elements in this particular enzyme species. These comparisons provide further insight into the principles governing DHFR-inhibitor interaction, in which the volume of the active site appears to determine the strength of inhibitor binding.

Amino Acid Sequence↗
PubMed1993

Preliminary crystallographic data for Pneumocystis carinii dihydrofolate reductase.

Dihydrofolate reductase from Pneumocystis carinii has been crystallized in a form suitable for high resolution X-ray diffraction studies. Recombinant enzyme that had been refolded following solubilization in guanidinium hydrochloride was crystallized as both a ternary complex with the cofactor NADPH and the inhibitor trimethoprim as well as a binary complex with NADPH. The two types of complex crystallized isomorphously from polyethylene glycol using sitting-drop vapour diffusion. The crystals were of space group P2(1) with unit cell parameters, a = 69.9 A, b = 43.6 A, c = 37.6 A, beta = 117.7 degrees, with one molecule per asymmetric unit. The crystals diffracted to 1.8 A resolution.

AIDS-Related Opportunistic Infections↗
PubMed1992

Crystallographic and biochemical studies of the (inactive) Lys-49 phospholipase A2 from the venom of Agkistridon piscivorus piscivorus.

Chemical, genetic, and structural studies have defined a critical role for Asp-49 in the calcium-mediated activation of extracellular phospholipases A2 (PLA2). In 1984, a new class of PLA2 was isolated in which this invariant aspartate was replaced with a lysine (Maragnore, J.M., Merutka, G., Cho, W., Welches, W., Kezdy, F.J., and Heinrikson, R.L. (1984) J. Biol. Chem. 259, 13839-13843; Maragnore, J.M., and Heinrikson, R.L. (1986) J. Biol. Chem. 261, 4797-4804). The enzymatic activity of Lys-49 PLA2s has been questioned based on biochemical, mutational, and structural studies (van den Bergh, C.J., Slotboom, A.J., Verheij, H.M., and de Haas, G.H. (1988) Eur. J. Biochem. 176, 353-357). In this paper, we describe the structures of two crystal forms of the Lys-49 PLA2 isolated from the venom of Agkistridon piscivorus piscivorus. The refined models, along with complementary biochemical analysis, clarify the structural basis for the enzymatic inactivity of Lys-49 proteins.

Amino Acid Sequence↗
PubMed1992

1.67-A X-ray structure of the B2 immunoglobulin-binding domain of streptococcal protein G and comparison to the NMR structure of the B1 domain.

The structure of the B2 immunoglobulin-binding domain of streptococcal protein G has been determined at 1.67-A resolution using a combination of single isomorphous replacement (SIR) phasing and manual fitting of the coordinates of the NMR structure of B1 domain of streptococcal protein G [Gronenborn, A. M., et al. (1991) Science 253, 657-661]. The final R value was 0.191 for data between 8.0 and 1.67 A. The structure described here has 13 residues preceding the 57-residue Ig-binding domain and 13 additional residues following it, for a total of 83 residues. The 57-residue binding domain is well-determined in the structure, having an average B factor of 18.0. Only residues 8-77 could be located in the electron density maps, with the ends of the structure fading into disorder. Like the B1 domain, the B2 domain consists of four beta-strands and a single helix lying diagonally across the beta-sheet, with a -1, +3 chi, -1 topology. This small structure is extensively hydrogen-bonded and has a relatively large hydrophobic core. These structural observations may account for the exceptional stability of protein G. A comparison of the B2 domain X-ray structure and the B1 domain NMR structure showed minor differences in the turn between strands and two and a slight displacement of the helix relative to the sheet. Hydrogen bonds between crystallographically related molecules account for most of these differences.

Amino Acid Sequence↗
PubMed1991

A novel, highly stable fold of the immunoglobulin binding domain of streptococcal protein G.

The high-resolution three-dimensional structure of a single immunoglobulin binding domain (B1, which comprises 56 residues including the NH2-terminal Met) of protein G from group G Streptococcus has been determined in solution by nuclear magnetic resonance spectroscopy on the basis of 1058 experimental restraints. The average atomic root-mean-square distribution about the mean coordinate positions is 0.27 angstrom (A) for the backbone atoms, 0.65 A for all atoms, and 0.39 A for atoms excluding disordered surface side chains. The structure has no disulfide bridges and is composed of a four-stranded beta sheet, on top of which lies a long helix. The central two strands (beta 1 and beta 4), comprising the NH2- and COOH-termini, are parallel, and the outer two strands (beta 2 and beta 3) are connected by the helix in a +3x crossover. This novel topology (-1, +3x, -1), coupled with an extensive hydrogen-bonding network and a tightly packed and buried hydrophobic core, is probably responsible for the extreme thermal stability of this small domain (reversible melting at 87 degrees C).

Amino Acid Sequence↗
PubMed1986

Crystallization and preliminary diffraction studies of the Lys-49 phospholipase A2 from Agkistrodon piscivorus piscivorus.

Previous chemical and structural studies have proposed a major role for Asp-49 in the calcium-mediated activation of phospholipases A2. Recently, a new class of phospholipases A2 has been characterized with a lysine in the place of aspartate at position 49 (Maraganore, J. M., Merutka, G., Cho, W., Welches, W., Kézdy, F. J., and Heinrikson, R. L. (1984) J. Biol. Chem. 259, 13839-13843; Maraganore, J. M., and Heinrikson, R. L. (1986) J. Biol. Chem. 261, 4797-4804). Although both the Lys-49 and Asp-49 phospholipases require calcium for enzymatic activity, the Lys-49 enzymes appear to be unique in their ability to bind phospholipids prior to undergoing calcium-mediated activation. We have successfully crystallized the Lys-49 phospholipase A2 from the venom of the American cottonmouth water moccasin (Agkistrodon piscivorus piscivorus). The crystals are tetragonal, the space group being P4(1)2(1)2 or P4(3)2(1)2 with unit cell dimensions of a = b = 71.05 A, and c = 57.76 A. There is only one molecule in the asymmetric unit and the crystals provide good quality diffraction data to 2.2 A.

Crystallization↗
PubMed1985

Crystals of crotoxin suitable for high resolution x-ray diffraction analysis.

The phospholipasic presynaptic neurotoxin, crotoxin, has been crystallized in a morphology suitable for single crystal x-ray diffraction analysis. The conditions for growth and the unit cell parameters (P4(1)22 or P4(3)22, a = b = 38.5 A, c = 256.9 A, 1 molecule/asymmetric unit) are similar to the very thin plate-like crystals which have been studied with electron diffraction and electron microscopy by Chiu and his colleagues (Jeng, T.-W., Chiu, W., Zemlin, F., and Zeitler, E. (1984) J. Mol. Biol. 175, 93 - 97). These two macroscopic crystal morphologies of what is likely to be a very similar, if not identical, lattice structure will permit the complementary application of electron diffraction/microscopy and x-ray diffraction to understanding the structural basis of the interactions between a phospholipasic neurotoxin and its membrane target.

Animals↗
PubMed1981

Glucose-6-phosphate isomerase.

Glucose-6-phosphate isomerase (EC 5.3.1.9) is a dimeric enzyme of molecular mass 132000 which catalyses the interconversion of D-glucose-6-phosphate and D-fructose-6-phosphate. The crystal structure of the enzyme from pig muscle has been determined at a nominal resolution of 2.6 A. The structure is of the alpha/beta type. Each subunit consists of two domains and the active site is in both the domain interface and the subunit interface (P.J. Shaw & H. Muirhead (1976), FEBS Lett. 65, 50-55). Each subunit contains 13 methionine residues so that cyanogen bromide cleavage will produce 14 fragments, most of which have been identified and at least partly purified. Sequence information is given for about one-third of the molecule from 5 cyanogen bromide fragments. One of the sequences includes a modified lysine residue. Modification of this residue leads to a parallel loss of enzymatic activity. A tentative fit of two of the peptides to the electron density map has been made. It seems possible that glucose-6-phosphate isomerase, triose phosphate isomerase and pyruvate kinase all contain a histidine and a glutamate residue at the active site.

Amino Acid Sequence↗
PubMed1977

Structure of a dinucleoside phosphate--drug complex as model for nucleic acid--drug interaction.

The crystal structure of a 3:2 complex of the frameshift mutagen proflavine with the dinucleoside phosphate cytidylyl-3'5'-guanosine has been determined. The complex has one drug molecule intercalated between Watson--Crick base pairs of the nucleotide duplex. The other two proflavine molecules are bound to the exterior of the miniature double helix. The orientation of the base pairs in this miniature double helix has aspects similar to that found in RNA 11.

Acridines↗