Rapid postsynthetic destruction of unstable haemoglobin Bushwick

Rieder, Ronald F.; Wolf, Didier; Clegg, J. B.; Lee, S. L.

doi:10.1038/254725a0

Cited by 51 publications

(5 citation statements)

References 22 publications

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“…In support of our findings comes the well-known ability of human reticulocytes to degrade newly made free CI chains by proteolysis, within a few minutes of synthesis [4, [17][18][19][20][21][22]. The obtained 12-mjn value for the half-life of puromycyl peptides in normal human erythroid cells is very close to the value of 15-20 min found by Etlinger and Goldberg in rabbit reticulocytes [lo].…”

Section: Discussionsupporting

confidence: 89%

Rapid proteolysis of puromycyl peptides in non‐thalassaemic and thalassaemic erythroid cells

Chalevelakis¹,

Lyberatos²,

Yalouris³

et al. 1984

Eur J Clin Investigation

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The proteolytic degradation of labelled pyromycyl polypeptides was investigated in human intact erythroid cells derived from the bone marrow of eight non-thalassaemic patients and the peripheral blood of eleven thalassaemics (eight splenectomized beta thalassaemia heterozygotes and three sickle-cell beta thalassaemics). These abnormal polypeptides are rapidly degraded to soluble trichloroacetic-acid (TCA) fragments with a half-life of 12 min both in bone marrow and peripheral blood. This comes very close to the half-life reported for the puromycyl peptide degradative system in rabbit reticulocytes (15 min). The relationship of the present proteolytic system to the ATP-dependent one, described in rabbit reticulocytes, and to that responsible for the free alpha-chain degradation in beta thalassaemia is discussed.

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Section: Discussionsupporting

confidence: 89%

Rapid proteolysis of puromycyl peptides in non‐thalassaemic and thalassaemic erythroid cells

Chalevelakis¹,

Lyberatos²,

Yalouris³

et al. 1984

Eur J Clin Investigation

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“…This mutation would result in the conversion of the codon GGC, for Gly-558, to GUC. Gly to Val mutations, although only occasionally reported, have been identified previously at positions 24 and 74 in the hemoglobin 0-chain (Huisman et al, 1971;Rieder et al, 1975).…”

Section: Discussionmentioning

confidence: 90%

Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity

Henriksen

Mann²

1989

Biochemistry

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Thrombin Quick II is one of two dysfunctional forms of thrombin derived from the previously described congenital dysprothrombin prothrombin Quick. Thrombin Quick II does not clot fibrinogen, hydrolyze p-nitroanilide substrates of thrombin, or bind N2-[5-(dimethylamino)naphthalene-1-sulfonyl]arginine N,N-(3-ethyl-1,5-pentanediyl)amide, a high-affinity competitive inhibitor of thrombin. To determine the structural alteration in thrombin Quick II, the reduced, carboxymethylated protein was hydrolyzed by a lysyl endopeptidase. A peptide not present in a parallel thrombin hydrolysate was identified by reverse-phase chromatography. The peptide was purified by rechromatography and subjected to Edman degradation which showed that Gly-558 of human prothrombin had been replaced by Val. This corresponds to a point mutation of the Gly codon GGC to GUC. This Gly residue, which is highly conserved in the chymotrypsin family of serine proteases, forms part of the substrate binding pocket for bulky aromatic and basic side chains in chymotrypsin and trypsin, respectively. However, in porcine elastase 1, the corresponding residue is threonine. Consistent with the identified structural alteration, thrombin Quick II incorporates [3H]diisopropyl fluorophosphate stoichiometrically and hydrolyzes the elastase substrate succinyl-Ala-Ala-Pro-Leu-p-nitroanilide with a relative kcat/KM of 0.14 when compared to thrombin. This results from a 3-fold increase in KM and a 2.5-fold decrease in kcat for thrombin Quick II when compared to thrombin acting on the same substrate. These results and those of other investigators studying mutant trypsins support the conclusion that the catalytic activity of serine proteases is very sensitive to structural alterations in the primary substrate binding pocket.

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“…Access to various AAS formulations is unregulated, and these formulations can have active metabolites that are 5–15 times more potent than standard testosterone replacement therapies. Animal studies have demonstrated that exogenous AAS administration has deleterious cardiovascular effects including indirect neurohormonal activation and direct androgenic receptor stimulation resulting in hypertension, myocyte hypertrophy and extracellular fibrosis, apoptotic cell death, premature coronary artery disease, and arrhythmogenesis . Multiple reports of exogenous AAS have been linked with adverse cardiovascular outcome in humans, and long‐term testosterone use may lead to hypertension and stroke, cardiac diastolic and systolic dysfunction, coronary artery disease, arrhythmias, and sudden death …”

Section: Discussionmentioning

confidence: 99%

Strong muscles, weak heart: testosterone‐induced cardiomyopathy

et al. 2019

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Exogenous anabolic androgen steroid use is associated with adverse cardiovascular outcomes. A 53‐year‐old bodybuilder presented with 3 months of exertional dyspnoea. Physical examination showed tachycardia and pan‐systolic murmur; an echocardiogram showed a left ventricular ejection fraction (EF) of 15%. Evaluations included normal coronary angiogram, iron panel and thyroid studies, a negative viral panel (human immunodeficiency virus, Lyme disease, and hepatitis), and urine toxicology. He admitted to intramuscular anabolic steroid use; his testosterone level was 30 160.0 ng/dL (normal 280–1100 ng/dL). In addition to discontinuation of anabolic steroid use, he was treated with guideline‐directed heart failure medical therapy. Repeat echocardiogram at 6 months showed an EF of 54% and normalized testosterone level of 603.7 ng/dL. Anabolic steroid use is a rare, reversible cause of cardiomyopathy in young, otherwise healthy athletes; a high index of suspicion is required to prevent potentially fatal side effects.

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Rapid postsynthetic destruction of unstable haemoglobin Bushwick

Cited by 51 publications

References 22 publications

Rapid proteolysis of puromycyl peptides in non‐thalassaemic and thalassaemic erythroid cells

Rapid proteolysis of puromycyl peptides in non‐thalassaemic and thalassaemic erythroid cells

Substitution of valine for glycine-558 in the congenital dysthrombin thrombin Quick II alters primary substrate specificity

Strong muscles, weak heart: testosterone‐induced cardiomyopathy

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