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Biomedical subjects

R W Carrell

Publications and source records attributed to R W Carrell.

At least 145 records · Page 8Linked to original sources
PubMed1983

Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder.

Our previous studies predicted a functional relationship between the plasma proteins alpha 1-antitrypsin and antithrombin III. To elucidate this relationship we investigated the plasma of a 14-year-old boy who had died from an episodic bleeding disorder. A variant alpha 1-antitrypsin was identified in which the methionine at position 358 had been replaced by an arginine. This had converted the alpha 1-antitrypsin from its normal function as an inhibitor of elastase to that of an inhibitor of thrombin. This finding indicates that the reactive center of alpha 1-antitrypsin is methionine 358, which acts as a bait for elastase, just as the normal reactive center of antithrombin III is arginine 393, which acts as a bait for thrombin. The independence of the new thrombin inhibitor from heparin control explains the bleeding disorder; it also indicates that heparin normally acts directly on antithrombin III, revealing its inherent inhibitory activity. The episodic nature of the bleeding was a consequence of the mutant protein's being an acute-phase reactant, the level of which increased several-fold after trauma.

Adolescent↗
PubMed1983

The reactive site of alpha 1-antitrypsin is C-terminal, not N-terminal.

alpha 1-Antitrypsin recovered from trypsin-alpha 1-antitrypsin complexes was shown to be a mixture of two peptides which remained associated in 6 M guanidine and in 1% acetic acid, but were separated by SDS-polyacrylamide gel electrophoresis. The larger peptide had an Mr of 47 000 and gave low yields on end-group analysis; the smaller had an Mr of 4000 and was the C-terminal 36-residue fragment of alpha 1-antitrypsin. These results explain the consistent but erroneous finding of a reactive site near the N-terminus of alpha 1-antitrypsin, and confirm that the reactive site is 36 residues from the C-terminus.

Amino Acid Sequence↗
PubMed1983

Translation and processing of normal (PiMM) and abnormal (PiZZ) human alpha 1-antitrypsin.

Human liver mRNA isolated from subjects phenotyped as homozygous PiMM or PiZZ alpha 1-antitrypsin, was translated in a reticulocyte cell-free system, and alpha 1-antitrypsin identified by immunoprecipitation. In the presence of dog pancreas membranes the translated alpha 1-antitrypsin appeared as a larger product. Treatment with endo-beta-N-glucosaminidase yielded a protein smaller than the reticulocyte translated product, presumably due to removal of the N-terminal signal sequence by membranes and sugar residues by endo-beta-N-glucosaminidase. Quantitation of alpha 1-antitrypsin translated from PiMM and PiZZ livers suggests that both mRNA species were present at the same cellular concentration, and that processing to the core glycosylation stage proceeded at identical rates.

Animals↗
PubMed1983

Rapid proteolysis of unstable globins in human bone marrow.

To determine whether human red cells contain a proteolytic system capable of rapidly degrading unstable proteins, the fate of pulse-labelled puromycyl polypeptides was investigated. In erythroid bone marrow cells these unstable polypeptides were degraded to TCA-soluble fragments with a mean half-life of 4 . 5 min. However, in peripheral blood reticulocytes no proteolysis was observed, indicating that this activity declines as the red cell matures.

Bone Marrow↗
PubMed1983

Two unstable hemoglobins in one individual: Hb Atlanta (beta 75 Leu leads to Pro) and Hb Coventry (beta 141 Leu deleted).

A 25-year-old male had a life long history of a hemolytic anemia which was shown to be due to the presence of an unstable hemoglobin, Hb Atlanta beta 75 Leu leads to Pro. Two dimensional peptide maps of isopropanol precipitated globin also showed the presence of a second variant, Hb Coventry beta 141 Leu deleted. HPLC separation of the tryptic peptides consistently demonstrated both the abnormal and normal beta 9 and beta 14 peptides in the digest of total globin. Neither of the abnormal peptides was apparent on similar maps of globin from his parents or his two siblings. The proportion of the variants measured from the peptide maps was 11% beta-Coventry, 34% beta-Atlanta and the remainder beta-A. The possible basis for the presence of three beta-globins is discussed and it is concluded that this is likely to be due to some mechanism other than a beta-delta cross-over.

Adult↗
PubMed1982

In vitro synthesis of M and Z forms of human alpha 1-antitrypsin.

mRNA was prepared from autopsy liver samples from a homozygote for alpha 1-antitrypsin deficiency (PiZZ) and from a normal (PiMM) subject. Both preparations gave equivalent synthesis of alpha 1-antitrypsin in a wheat germ cell-free system. This suggests that the deficiency of plasma alpha 1-antitrypsin associated with the Z variant is due to a failure of processing and secretion of the protein rather than of its synthesis. It is likely that it is the resultant intracellular accumulation of the Z protein rather than a deficiency of protease inhibitor that is the primary cause of the liver pathology associated with this variant.

Adolescent↗
PubMed1982

Structure and variation of human alpha 1-antitrypsin.

The sequence of alpha 1-antitrypsin is in keeping with its role as a tissue scavenger of leukocyte elastase. Two abnormal variants commonly present in Europeans cause a deficiency that predisposes them to a progressive loss of lung elasticity. The nature of the reactive centre helps explain why cigarette smoking greatly accelerates the onset and severity of this degenerative process to give the disease emphysema.

Amino Acid Sequence↗
PubMed1982

alpha 1-Antitrypsin microheterogeneity. Isolation and physiological significance of isoforms.

alpha 1-Antitrypsin has a microheterogeneity evident on isoelectric focusing as three major and several minor bands. We have identified the carbohydrate structures of the major bands; band 6 (isoform I) has three bi-antennary sidechains, band 4 (isoform II) has two bi- and one tri-antennary and band 2 (isoform III) has one bi- and two tri-antennary sidechains. The identity of the isoforms with the bands permitted their measurement in plasma by photometric scanning of the electrofocused gels. In healthy controls the levels of isoforms I, II and III were relatively constant and in the proportions of 5, 4 and 1, respectively. A marked change occurred during inflammation and oestrogen stress with isoforms II and III accounting for most of the increase in alpha 1-antitrypsin. One possible consequence of the changed proportions was shown to be the increased catabolism of the partially desialylated tri-antennary isoforms compared to that of the predominant bi-antennary form of the healthy individual.

Animals↗
PubMed1981

Heterozygous alpha 1-antitrypsin deficiency: a longitudinal lung function study.

alpha 1-antitrypsin phenotypes were determined in 906 adults from an entire community; 4.9 percent were heterozygotes (Pi MZ) for severe deficiency and 8 percent were heterozygotes (Pi MS) for mild deficiency. Lung function both in cross-section and over a period of three years was examined in those subjects with the two heterozygote deficiency phenotypes and compared with the lung function of those with the normal Pi M phenotype. FVC and FEV1 were standardised for age, sex, height, race, smoking habit and quantum, and respiratory symptoms. Using techniques of multivariate analysis and rigorous matched pairs there was no evidence of a deterioration in lung function in Pi MS or Pi MZ subjects. The tests used did not exclude the possibility of minor alveolar abnormalities but the results do allow the confident counselling of heterozygotes that they can look forward to full respiratory health.

Adult↗