Biosynthesis of astromicin and related antibiotics. II. Biosynthetic studies with blocked mutants of Micromonospora olivasterospora

An inosamine-idiotrophic mutant, KY11559, which produced no astromicin unless scyllo-inosamine was added to the fermentation medium, was isolated from Micromonospora olivasterospora. Biotransformation studies were performed with resting cells of this mutant and compounds assumed to be precursors of 1,4-diaminocyclitol (fortamine). Scyllo-inosose, scyllo-inosamine and FU-10 were converted to astromicin. A number of mutants blocked in the biosynthesis of astromicin were developed from M. olivasterospora, and the intermediates accumulated by these mutants were isolated and identified. Twenty-five blocked mutants were classified into 10 groups, based on their complementation patterns by cosynthesis experiments. Further, utilizing these blocked mutants and the isolated compounds, biotransformation analyses were performed. The results showed that the amination at position 4 in fortamine occurred after formation of the pseudodisaccharide. Subsequently, the aminosugar and aminocyclitol moieties were aminated, methylated, dehydroxylated, epimerized and acylated to produce astromicin. Thus it was demonstrated that the astromicin biosynthetic pathway has a unique feature which is not found in the biosynthesis of other aminoglycoside antibiotics.     

Biosynthesis of astromicin and related antibiotics. I. Biosynthetic studies by bioconversion experiments

Biosynthesis of astromicin, a unique pseudodisaccharide aminoglycoside antibiotic containing 1,4-diaminocyclitol component, was investigated by isolating a variety of possible precursor compounds from mutants of Micromonospora olivasterospora in which biosynthetic pathways for astromicin were blocked. Washed mycelia of M. olivasterospora mutants converted these compounds to astromicin, which was detected by thin-layer chromatography. Since astromicin possesses one glycyl and three methyl groups, [14C]glycine and [14C]methionine should be incorporated into precursors to form astromicin. To confirm the biosynthetic pathway, formation of labeled astromicin from the precursors was examined using [1-14C]-glycine or [methyl-14C]methionine. From above results, we propose the biosynthetic pathway for astromicin as shown in Fig. 2.     

A case of recurrent multiple cerebral infarctions with protein C abnormality

A 38-year-old man of recurrent episodes of multiple cerebral infarctions with protein C abnormality was reported. He had six episodes of visual disturbance within a year. The neurological examination revealed bilateral visual loss and impaired visual field except for small central area. However, there were no abnormalities in the deep tendon reflexes and muscle strength of all extremities and cerebellar examinations. CT scan revealed multiple low density areas in the bilateral posterior lobes, and cerebral angiography demonstrated the severe stenosis of the ganglionic portion and the supraclinoid portion of the right internal carotid artery. Plasma levels of antithrombin-III activity, plasminogen activity, protein C activity, protein C antigen and protein S antigen were 105, 106, 28, 166 and 120%, respectively. Because only protein C activity decreased markedly, a diagnosis of protein C abnormality was established. We started warfarin therapy under the administration of concentrates of factor IX complex, since then there has been no cerebral accident.     

Skeletal concentrations of lead in ancient Peruvians.

The level of biologic lead (expressed as the ratio of atomic lead to atomic calcium) in bones of Peruvians buried 1600 years ago was found to be 3 x 10(-8), as compared to 2100 to 3500 x 10(-8) in the bones of present-day residents of England and the United States. The ratio of barium to calcium was 2 to 3 x 10(-6) in bones of ancient Peruvians and present-day Americans. Barium and lead have similar morphologic distributions in organisms, so this discrepancy for lead must result from overexposure of present-day people to industrial lead and not from natural variations. The magnitude of this discrepancy has been confirmed by two different lines of investigation not reported in this article. This new evidence suggests that natural interactions of lead in human cells have not yet been determined because reagents, nutrients and controls used in laboratory and field studies have been contaminated with lead far in excess of naturally occurring levels.     

Intramural Hematoma of the Cecum as the Lead Point of Intussusception in an Elderly Patient with Hemophilia A: Report of a Case

Hemophilia A is a congenital bleeding disorder characterized by a deficiency of coagulation factor VIII. Intramural hematoma of the colon is a very rare complication of this disease. We report a case of intramural hematoma of the cecum serving as the lead point of intussusception in a 65-year-old man with hemophilia A. The patient presented with right-sided abdominal pain and bloody stool. Palpation of his abdomen revealed a fist-sized mass. Abdominal computed tomography (CT) showed a circular mass with concentric rings, consistent with an intussuscepted intestine. Because his activated partial thromboplastin time (APTT) was prolonged, we gave him a continuous infusion of factor VIII during and after surgery. Laparotomy revealed an irreducible colo-colic intussusception and we identified a cecal hematoma as the lead point. After an unsuccessful attempt at Hutchinson's maneuver, we performed right colectomy. We report this case to illustrate the necessity of monitoring APTT in patients with hemophilia A who undergo surgery.