Amino acid metabolism in Acetobacter suboxydans

Nutritional studies with Acetobacter suboxydans indicated that when isoleucine, lysine, methionine, serine and arginine were singly omitted from a complete amino acid mixture, no growth was obtained. However, the organism could grow on single amino acids like glutamic acid, histidine and proline. No growth was obtained with ammonium sulfate as the sole nitrogen source. An investigation on the cause for the apparent requirement for isoleucine was made. When valine was added to a synthetic medium containing histidine, glutamic acid, proline and ammonium sulfate no growth was obtained. Valine appeared to inhibit growth, an effect which could be reversed by addition of isoleucine. Cell-free extracts of the organism synthesize both valine and isoleucine from acetolactate and acetohydroxybutyrate respectively. The amounts of the two amino acids synthesized from different intermediates were determined. A study of the mechanism of growth inhibition due to valine was initiated. U-C¹⁴ threonine was incorporated into isoleucine by growing cells. The first step in the biosynthesis of isoleucine from threonine is the deamination of the latter to ?-ketobutyrate. This enzyme, threonine deaminase, was precipitated from cell-free extracts at 50 percent saturation with ammonium sulfate. Using this fraction, it was found that the activity of the deaminase was competitively inhibited by valine and isoleucine. Although isoleucine repressed the synthesis of the deaminase, valine did not. Therefore one mechanism by which valine inhibits growth of the organism is by feed-back inhibition of the threonine deaminase thereby limiting isoleucine biosynthesis. This is evident by an apparent requirement for isoleucine when valine is present in the growth medium. No inhibition of the transport of isoleucine across the cell wall was observed. Mutants of Acetobacter suboxydans have been isolated which are prototrophic towards isoleucine and resistant to growth inhibition by valine. Some of these mutants possess a threonine deaminase which is not sensitive to valine or isoleucine

PubChem3D: Similar conformers

<p>Abstract</p> <p>Background</p> <p>PubChem is a free and open public resource for the biological activities of small molecules. With many tens of millions of both chemical structures and biological test results, PubChem is a sizeable system with an uneven degree of available information. Some chemical structures in PubChem include a great deal of biological annotation, while others have little to none. To help users, PubChem pre-computes "neighboring" relationships to relate similar chemical structures, which may have similar biological function. In this work, we introduce a "Similar Conformers" neighboring relationship to identify compounds with similar 3-D shape and similar 3-D orientation of functional groups typically used to define pharmacophore features.</p> <p>Results</p> <p>The first two diverse 3-D conformers of 26.1 million PubChem Compound records were compared to each other, using a shape Tanimoto (ST) of 0.8 or greater and a color Tanimoto (CT) of 0.5 or greater, yielding 8.16 billion conformer neighbor pairs and 6.62 billion compound neighbor pairs, with an average of 253 "Similar Conformers" compound neighbors per compound. Comparing the 3-D neighboring relationship to the corresponding 2-D neighboring relationship ("Similar Compounds") for molecules such as caffeine, aspirin, and morphine, one finds unique sets of related chemical structures, providing additional significant biological annotation. The PubChem 3-D neighboring relationship is also shown to be able to group a set of non-steroidal anti-inflammatory drugs (NSAIDs), despite limited PubChem 2-D similarity.</p> <p>In a study of 4,218 chemical structures of biomedical interest, consisting of many known drugs, using more diverse conformers per compound results in more 3-D compound neighbors per compound; however, the overlap of the compound neighbor lists per conformer also increasingly resemble each other, being 38% identical at three conformers and 68% at ten conformers. Perhaps surprising is that the average count of conformer neighbors per conformer increases rather slowly as a function of diverse conformers considered, with only a 70% increase for a ten times growth in conformers per compound (a 68-fold increase in the conformer pairs considered).</p> <p>Neighboring 3-D conformers on the scale performed, if implemented naively, is an intractable problem using a modest sized compute cluster. Methodology developed in this work relies on a series of filters to prevent performing 3-D superposition optimization, when it can be determined that two conformers cannot possibly be a neighbor. Most filters are based on Tanimoto equation volume constraints, avoiding incompatible conformers; however, others consider preliminary superposition between conformers using reference shapes.</p> <p>Conclusion</p> <p>The "Similar Conformers" 3-D neighboring relationship locates similar small molecules of biological interest that may go unnoticed when using traditional 2-D chemical structure graph-based methods, making it complementary to such methodologies. The computational cost of 3-D similarity methodology on a wide scale, such as PubChem contents, is a considerable issue to overcome. Using a series of efficient filters, an effective throughput rate of more than 150,000 conformers per second per processor core was achieved, more than two orders of magnitude faster than without filtering.</p