Characterization of the common genetic defect in humans deficient in debrisoquine metabolism

In population studies of individuals given the antihypertensive drug debrisoquine, two distinct phenotypes have been described: extensive metabolizers excrete 10-200 times more of the urinary metabolite 4-hydroxydebrisoquine than poor metabolizers. In family studies the poor-metabolizer phenotype behaves as an autosomal recessive trait with an incidence between 5% and 10% in the white population of Europe and North America, and extends to the deficient metabolism of more than 20 commonly prescribed drugs. Clinical studies have shown that such individuals are at high risk for the development of adverse side effects from these and probably many other drugs. Here we show that poor metabolizers have negligible amounts of the cytochrome P450 enzyme P450db1. We have cloned the human P450db1 complementary DNA and expressed it in mammalian cell culture. Furthermore, by directly cloning and sequencing cDNAs from several poor-metabolizer livers, we have identified three variant messenger RNAs that are products of mutant genes producing incorrectly spliced db1 pre-mRNA, providing a molecular explanation for one of man's most commonly defective genes (frequency of mutant alleles 35-43%).     

Studies on substrate specificity of X-prolyl dipeptidyl-aminopeptidase during new chromogenic substrates, X-Y-p-nitroanilides

Substrate specificity of X-prolyl dipeptidyl-aminopeptidase (dipeptidyl aminopeptidase IV) was examined by using newly synthesized 8 chromogenic substrates, X-Y-p-nitroanilides. Homogeneous enzyme from human submaxillary gland hydrolyzed glycylproline p-nitroanilide almost specifically, except alanylalanine p-nitroanilide which had 11% activity.     

Stabilization of microtubule dynamics at anaphase onset promotes chromosome segregation

Microtubules of the mitotic spindle form the structural basis for chromosome segregation. In metaphase, microtubules show high dynamic instability, which is thought to aid the 'search and capture' of chromosomes for bipolar alignment on the spindle. Microtubules suddenly become more stable at the onset of anaphase, but how this change in microtubule behaviour is regulated and how important it is for the ensuing chromosome segregation are unknown. Here we show that in the budding yeast Saccharomyces cerevisiae, activation of the phosphatase Cdc14 at anaphase onset is both necessary and sufficient for silencing microtubule dynamics. Cdc14 is activated by separase, the protease that triggers sister chromatid separation, linking the onset of anaphase to microtubule stabilization. If sister chromatids separate in the absence of Cdc14 activity, microtubules maintain high dynamic instability; this correlates with defects in both the movement of chromosomes to the spindle poles (anaphase A) and the elongation of the anaphase spindle (anaphase B). Cdc14 promotes localization of microtubule-stabilizing proteins to the anaphase spindle, and dephosphorylation of the kinetochore component Ask1 contributes to both the silencing of microtubule turnover and successful anaphase A.     

Sequence and analysis of chromosome 5 of the plant Arabidopsis thaliana

The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.     

Isolation ofβ 2-microglobulin from the urine of patients with itai-itai (Ouch-ouch) disease

Zusammenfassung Im 24-h-Urin von Frauen mit der seltenen Itai-itai-Krankheit wurde das gleiche ₂-mikroglobulin nachgewiesen, das auch bei chronischer Cadmium-Intoxikation ausgeschieden wird.     

A low molecular weight glycosaminoglycan from the human aorta

Summary A low mol.wt, dialyzable glycosaminoglycan was isolated from human aorta and was found to be homogeneous on 2 dimensional electrophoresis. As judged by its electrophoretic mobilities and its hydrolysis by chondroitin sulfatase ABC, it was concluded that this hitherto unknown glycosaminoglycan is an oversulfated chondroitin sulfate.This study was supported by grants from the National Institutes of Health (GM-10374, HL-13262), U.S. Public Health Service.