Biomedical subjects

K Padmakumar

Publications and source records attributed to K Padmakumar.

9 recordsLinked to original sources

PubMed2006

Kahalalide derivatives from the Indian sacoglossan mollusk Elysia grandifolia.

Two new cyclic depsipeptide derivatives, kahalalides R (1) and S (2), together with two known congeners, kahalalides F (3) and D (4), were isolated from the Indian sacoglossan mollusk Elysia grandifolia. The structures of the new compounds were unambiguously established on the basis of NMR spectroscopic (1H, 13C, COSY, HMBC) and mass spectrometric (FABMS, ESIMS, MALDI-TOF/PSD) data, which also included Marfey amino acid analyses. The new derivative kahalalide R was found to exert comparable or even higher cytotoxicity than the potential drug candidate kahalalide F toward the MCF7 human mammary carcinoma cell line.

Animals↗

PubMed2005

Anion binding properties of reduced and oxidized iron-containing superoxide dismutase reveal no requirement for tyrosine 34.

We report the first spectroscopic observation of substrate analogue binding to the reduced state of iron superoxide dismutase from Escherichia coli (Fe(2+)SOD) and demonstrate that the pH dependence reflects inhibition of anion binding by ionized Tyr34, not loss of a positive contribution on the part of Tyr34's labile proton. This can also explain the pH dependence of the K(M) of Fe(2+)SOD. Thus, it appears that substrate binding to Fe(2+)SOD occurs in the second sphere and is not strongly coupled to hydrogen bond donation. Parallel investigations of substrate analogue binding to the oxidized state (Fe(3+)SOD) confirm formation of a six-coordinate complex and resolve the apparent conflict with earlier nuclear magnetic relaxation dispersion (NMRD) results. Thus, we propose that two F(-) ions can bind to the oxidized Fe(3+)SOD active site, either displacing the coordinated solvent or lowering its exchange rate with bulk solvent. We show that neutral Tyr34's unfavorable effect on binding of the substrate analogue N(3)(-) can be ascribed to steric interference, as it does not apply to the smaller substrate analogues F(-) and OH(-). Finally, we report the first demonstration that HS(-) can act as a substrate analogue with regard both to redox reactivity with FeSOD and to ability to coordinate to the active site Fe(3+). Indeed, it forms a novel green complex. Thus, we have begun to evaluate the relative importance of different contributions that Tyr34 may make to substrate binding, and we have identified a novel, redox active substrate analogue that offers new possibilities for elucidating the mechanism of FeSOD.

Amino Acid Substitution↗

PubMed2003

Proton-coupled electron transfer in Fe-superoxide dismutase and Mn-superoxide dismutase.

Fe-containing superoxide dismutase (FeSOD) and MnSOD are widely assumed to employ the same catalytic mechanism. However this has not been completely tested. In 1985, Bull and Fee showed that FeSOD took up a proton upon reduction [J. Am. Chem. Soc. 107 (1985) 3295]. We now demonstrate that MnSOD incorporates the same crucial coupling between electron transfer and proton transfer. The redox-coupled H(+) acceptor has been presumed to be the coordinated solvent molecule, in both FeSOD and MnSOD, however this is very difficult to test experimentally. We have now examined the most plausible alternative: that Tyr34 accepts a proton upon SOD reduction. We report specific incorporation of 13C in the C(zeta) positions of Tyr residues, assignment of the C(zeta) signal of Tyr34 in each of oxidized FeSOD and MnSOD, and direct NMR observations showing that in both cases, Tyr34 is in the neutral protonated state. Thus Tyr34 cannot accept a proton upon SOD reduction, and coordinated solvent is concluded to be the redox-coupled H(+) acceptor instead, in both FeSOD and MnSOD. We have also confirmed by direct 13C observation that the pK of 8.5 of reduced FeSOD corresponds to deprotonation of Tyr34. This work thus provides experimental proof of important commonalities between the detailed mechanisms of FeSOD and MnSOD.

Binding Sites↗

PubMed2001

Lattice-dictated conformers in bis(pyrazolyl)pyridine-based iron(II) complexes: Mössbauer, NMR, and magnetic studies.

Iron(II) complexes [FeL(2)](ClO(4))(2).CH(3)CN, [FeL(2)](BPh(4))(2).2CH(3)CN, and [FeL(2)](PF(6))(2) with an FeN(6) chromophore of the same ligand L (2,6-bis(3,5-dimethylpyrazol-1-ylmethyl)pyridine) and differing counterions have been made and their crystal and molecular structures determined. The first two crystallized in triclinic space group P(-)1, and the third, with PF(6)(-) anion in Ibca space group. The FeL(2) complex ions in all lattices have similarly distorted octahedral geometry. Variable-temperature Mössbauer spectra of [FeL(2)](ClO(4))(2).CH(3)CN and [FeL(2)](PF(6))(2) measured in the temperature range 1.7-300 K reveal temperature-dependent populations of two different spin states with increased amount of low-spin form at high temperatures, a phenomenon unlike the normal spin crossover behavior; this abnormal behavior is interpreted here as due to the presence of two different conformations. It is very interesting to note that the two different compounds have similar spectra, Mössbauer parameters, and temperature dependence. But the variable-temperature Mössbauer spectra of [FeL(2)](BPh(4))(2).2CH(3)CN in the range 20-300 K do not show the presence of such different species but exhibit a clear phase transition at approximately 200 K. This phase transition is further supported by SQUID measurements. The results of variable-temperature (1)H NMR in CD(3)CN and the solution susceptibility measurement of all complexes also support the presence of high-spin and low-spin forms in solution. Hence, the complex ion [FeL(2)](2+) exhibits a thermally driven interconversion between low-spin and a high-spin structural forms-a phenomenon observed in the solid and solution states due to ligand dynamics. This is not due to the well-known spin crossover phenomenon. These results are compared with the case of normal spin crossover seen in [FeL'(2)](ClO(4))(2) (L' = 2,6-(bis(pyrazol-1-ylmethyl)pyridine)).

Journal Article↗

PubMed2000

Hyperfine interaction in K2Ba[Fe(NO2)6].

Magnetic hyperfine splitting observed in the low temperature Mössbauer spectrum of potassium barium hexanitro ferrate(II), in the absence of any external field, is attributed to the 5T2g state of the central metal atom further split into a ground 5Eg state and a first excited 5B2g state under a distorted octahedral symmetry in contrast to the earlier prediction of 1A1g ground state on the basis of room temperature Mössbauer spectral and other properties. The central iron atom is coordinated to six nitrito groups (NO2-), having an oxidation state of +2. The temperature dependence of Mössbauer spectra is explained on the basis of electronic relaxation among the spin-orbit coupled levels of the 5Eg ground state. Various kinds of electronic relaxation mechanisms have been compared to explain the proposed mechanism. The observed temperature dependent spectra with varying internal magnetic field and line width can be explained by simple spin lattice relaxation.

Barium Compounds↗

PubMed1990

Lupus anticoagulants in systemic lupus erythematosus: prevalence and clinical associations.

The prevalence of lupus anticoagulant (LAC) and its relation with reported clinical associations has been determined in 55 patients with systemic lupus erythematosus (SLE) from northern India who were studied prospectively. Kaolin clotting time was used to screen for LAC, which was detected in seven (13%) of the patients. Significant associations were found between LAC and thrombotic events, onset of disease at an early age, and disease of shorter duration. No statistically significant association could be found between LAC and recurrent abortions, pulmonary hypertension, thrombocytopenia, and neurological manifestations. It is concluded that LAC is a useful marker for a subset of patients with SLE at risk of thromboembolic events.

Adolescent↗

PubMed1989

Coagulation abnormalities in systemic lupus erythematosus.

Coagulation profile was studied in 55 patients of systemic lupus erythematosus (SLE). Abnormal kaolin clotting time (KCT) was observed in fewer patients (12.9%) as compared to abnormal Russel's viper venom time (RVVT, 20.4%) or activated partial thromboplastin time (APTT, 32.7%). Prolonged prothrombin time (PT), observed in 7.3 per cent patients was not found to be a sensitive test for lupus anticoagulant (LAC). The correction of RVVT and KCT on addition of inosithin suggested a deficiency of platelet lipid factor in these patients. The initial value of uncorrected KCT in patient's plasma did not correlate with the amount of inosithin required for neutralisation. Occurrence of thromboembolic events was significantly associated with prolonged KCT. No other clinical feature showed significant association with any coagulation abnormality.

Adolescent↗

PubMed1988

Cerebellar ataxia in systemic lupus erythematosus: three case reports.

Three patients presented with cerebellar ataxia among 350 cases of systemic lupus erythematosus (SLE) seen over the last 14 years. Cerebellar signs were unilateral in one and bilateral in the other two patients. Other neurological findings were present in all three patients. One initially presented with only cerebellar ataxia; other features of SLE appeared a few years later. Lupus anticoagulant test was positive in one patient. Corticosteroids given in the early stages appeared to benefit these patients by ameliorating cerebellar dysfunction.

Adolescent↗

PubMedDate not supplied

Chemical defense of Mediterranean sponges Aplysina cavernicola and Aplysina aerophoba.

The Mediterranean sponges Aplysina aerophoba and A. cavernicola accumulate brominated isoxazoline alkaloids including aplysinamisin-1 (1), aerophobin-2 (2), isofistularin-3 (3) or aerothionin (4) at concentrations up to 10% of their respective dry weights. In laboratory feeding experiments employing the polyphagous Mediterranean fish Blennius sphinx crude extracts of both Aplysina sponges were incorporated into artificial fish food at their physiological concentrations (based on volume) and offered to B. sphinx in choice feeding experiments against untreated control food. In addition to the Aplysina sponges, extracts from nine other frequently occurring Mediterranean sponges were likewise included into the experiments. Both Aplysina species elicited strong feeding deterrence compared to the other sponges tested. Bioassay-guided fractionation of A. cavernicola yielded the isoxazoline alkaloids aerothionin (4) and aplysinamisin-1 (1) as well as the 3,4-dihydroxyquinoline-2-carboxylic acid (8) as major deterrent constituents when tested at their physiological concentrations as present in sponges. Aeroplysinin-1 (5) and dienone (6), however, which are formed in A. aerophoba and A. cavernicola from isoxazoline precursors through bioconversion reactions upon tissue injury showed no or only little deterrent activity. Fractionation of a crude extract of A. aerophoba yielded aerophobin-2 (2) and isofistularin-3 (3) as major deterrent constituents against B. sphinx. We propose that the isoxazoline alkaloids 1-4 of Mediterranean Aplysina sponges as well as the 3,4-dihydroxyquinoline-2-carboxylic acid (8) (in the case of A. cavernicola) act as defensive metabolites against B. sphinx and possibly also against other predators while the antibiotically active bioconversion products aeroplysinin-1 (5) and dienone (6) may protect sponges from invasion of bacterial pathogens.

Alkaloids↗