Biomedical subjects
Publications and source records attributed to W Vater.
Using two groups of substances (derivatives of 1,4-benzoquinone and azomethines) it was compared their effect on the microtubule formation in vitro and on experimental leukemias. 9 from the 28 substances tested acted cancerostatically, 4 substances inhibited microtubule assembly. 3 compounds (fluorenoneazomethines) revealed both effects.
It is known that histone H1 is able to cause the formation of double-walled microtubules from microtubule protein. Now, we demonstrate that in dependence on the mass ratio H1/microtubule protein upon addition of tubulin to short pieces of double-walled microtubules either their inner or their outer wall elongates resulting in normal microtubules or in macrotubules, respectively. Because of their genesis we suggest that macrotubules like double-walled microtubules (see Unger et al., Eur. J. Cell Biol. 46, 98-104 (1988)) expose those sides of tubulin dimers at their surface which usually form the lumen face of microtubules.
Some basic proteins enable microtubule protein to form special assembly products in vitro, known as double-walled microtubules. Using histones (H1, core histones) as well as the human encephalitogenic protein to induce the formation of double-walled microtubules, we made the following electron microscopic observations: (1) Double-walled microtubules consist of an "inner" microtubule which is covered by electron-dense material, apparently formed from the basic protein, and by a second tubulin wall. (2) The tubulin of the second wall seems to be arranged as protofilaments, surrounding the inner microtubule in a helical or ring-like manner. (3) The surface of double-walled microtubules lacks the projections of microtubule-associated proteins, usually found on microtubules. (4) In the case of protofilament ribbons (incomplete microtubules), H1 binds exclusively to their convex sides that correspond to the surface of microtubules. Zn2+-induced tubulin sheets, consisting in contrast to microtubules of alternately arranged protofilaments, are covered by H1 on both surfaces. Furthermore, multilayered sheet aggregates appeared. The results indicate that the basic proteins used interact only with that protofilament side which represents the microtubule surface. In accordance with this general principle, models on the structure of double-walled microtubules and multilayered tubulin sheets were derived.
In the presence of glycerol, microtubule proteins reassemble into both microtubules and protofilament ribbons with C- and S-shaped cross-section profiles. By means of electron micrographs of cross-sectioned assemblies, we have demonstrated that, during the steady state, the percentage of ribbons, especially of C-shaped ones, decreases in favour of the formation of microtubules. The following conversion modes are discussed: A, closure of the protofilament wall by increasing its curvature; B, lateral association of C-ribbons; C, completion of C-ribbons to microtubules by lateral association of tubulin; D, disassembly of ribbons and elongation of microtubules. We conclude that ribbon disassembly proceeding in an end-wise fashion and microtubule elongation is the favoured mode of conversion. Microtubule-associated proteins were found to be required for the steady-state conversions of ribbons into microtubules. In the absence of microtubule-associated proteins, C-ribbons associate laterally, forming S-ribbons. It is shown that the protofilaments of the counter-curved parts of S-ribbons have the same polarity.
By use of high glycerol and sodium chloride concentrations a microtubule protein (MTP) from porcine brain can be isolated that contains only a small portion of microtubule-associated proteins (MAPs). This "NaCl-MTP" possesses assembly properties similar to chromatographically purified tubulin.
The pathway of tubulin assembly is controlled by a lot of effectors. We summarize some of these effectors favouring the formation of microtubules or inducing several MT-aberrant, polymorphic structures. Both in vivo and in vitro, microtubules with different protofilament numbers were found. In vivo, microtubules are composed of 11-16 protofilaments. The protofilament number of microtubules formed in vitro varies from 8-17. We describe some effectors responsible for the diversity of the protofilament number in microtubules. Moreover, differences in the amino acid sequences of distinct tubulins should be taken into account, too. The protofilament number of an established microtubule can be still altered if activities of effectors or microenvironmental conditions are changed. Thus, the protofilament number of microtubules is a dynamic property based on the permanent tubulin exchange.
In order to demonstrate the effect of microtubule-associated proteins on the protofilament number of microtubules, we used different systems of microtubule formation in vitro in which these proteins are either functionally eliminated (by DNA or glycerol) or absent (purified tubulin). The results obtained by electron microscopy of ultrathin-sectioned material indicate that under standard conditions in the presence of microtubule-associated proteins microtubules are formed consisting predominantly of 14 protofilaments. In cases of deficiency of microtubule-associated proteins, the mean value of the protofilament number is lower, and the protofilament number within the microtubule population varies remarkably. On the other hand, the action of microtubule-associated proteins is enhanced by histones resulting in increased protofilament numbers. A model is proposed illustrating that the quality and the quantity of microtubule-associated proteins bound to microtubules determine the curvature between the protofilaments and restrict the variety of their binding angles. In this way the microtubule-associated proteins may be regarded as an important factor in determining the structural fidelity of microtubules.
Using indirect immunofluorescence the microtubule system of slime molds has been investigated with antitubulin- and anti-MAP-antibodies. An extended cytoplasmic microtubule (MT) network with nucleus associated organells as centres can be visualized. The spindle apparatus with some astral fibres, the central spindle and the spindle pole bodies is stained in mitotic cells. In slime molds like in higher eucaryots MTs are sensitive against cold and MT-poison treatment, the MTs are composed of tubulin and MAP's, and tubulin is cross reactive with pig brain tubulin.
Michael-addition of 3-aminocrotonic acid ester 7 to aralkylidene acetoacetic acid esters 6 is followed by ring closure to give novel 4-aryl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylates 8 with non-identical ester functions. In the series of 3-nitrophenyl derivatives (8, Ar=3-nitrophenyl) the pharmacological activities (coronary vasodilation, antihypertensive activity) of the asymmetrically substituted derivatives are shown to be superior to those of the corresponding symmetrically substituted derivatives in many cases. One representative of this class 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009, No. 3) was selected for further development as an antihypertensive drug.
Replacement of the 2-alkyl group by amino in the structure of cardiovascular 4-aryl-2,6-dialkyl-1,4-dihydropyridine-3,5-dicarboxylates 1 is tolerated without loss of antihypertensive activity. The rules found for the substitution of the aromatic ring and the ester functions in 1 still hold for the novel 2-amino-1,4-dihydropyridines 6, 7 and 9 obtained by Michael addition of acetamidines to alpha, beta-unsaturated enones. 2-Dialkylamino-3,4-dihydropyridines 11 surprisingly also show good antihypertensive activity. In this case a displacement of the double bond in the heterocycle must also be taken into account. A 2-trifluoromethyl substitution in the phenyl residue and ester groups with low lipophilicity are optimal in this series.
There are only few data about the microbial contents in the workrooms of pharmacies. Up to now, neither the kinds of bacteria and yeasts encountered, nor their resistance has been determined. The "personal hygiene of the staff' is studied on the example of their hands, towels and protective clothes. The kinds of bacteria found on surfaces used for pharmaceutical work are analysed. Proposals for limiting the germ content in the air are commented upon. Health measures are elaborated on the basis of the results from the present investigation.
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In the series of 1,4-dihydro-2,6-dimethyl-4-nitrophenyl-pyridine-3,5-dicarboxylates the vasodilating action (increase of O2-saturation in the coronary sinus of the dog) is found to be dependent on the position of the nitro function (ortho and meta superior to para) and on the nature of the ester group. One representative, niludipin (BAY a 7168, No. 17; bis(2-propoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate) was selected for further pharmacological studies.
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