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PubMed1987

Protamine sulfate inhibits mitogenic activities of the extracellular matrix and fibroblast growth factor, but potentiates that of epidermal growth factor.

Protamine sulfate, an inhibitor of angiogenesis in vivo, markedly inhibits the ability of angiogenic factors such as acidic or basic fibroblast growth factor (aFGF, bFGF) to stimulate the proliferation in vitro of either BHK-21 cells or vascular endothelial cells. The inhibition is reversible, and cells remain viable even after prolonged exposure to protamine sulfate. Protamine sulfate inhibits the mitogenic effects of both growth factors by preventing them from binding to their common cell surface receptors. It also inhibits the mitogenic activity of the extracellular matrix produced by bovine corneal endothelial cells. This substrate has been shown in previous studies to replace the requirement for FGF of many cell types. In contrast, protamine sulfate potentiates the mitogenic activity of epidermal growth factor (EGF). This indicates that protamine sulfate also acts at cellular sites which are not associated with FGF receptors.

Animals↗

PubMed2006

Sperm nuclear basic proteins of two closely related species of Scorpaeniform fish (Sebastes maliger, Sebastolobus sp.) with different sexual reproduction and the evolution of fish protamines.

In this paper, we present a review of sperm nuclear basic proteins (SNBPs) in teleost fish. The distribution of the three basic groups of SNBPs [histone (H)-type, protamine-like (PL)-type and protamine (P)-type], their evolution and possible relation to the mode of fertilization are described. In this regard, we have characterized the SNBPs from two closely related species of Scorpaeniform fish: internally fertilizing Sebastes maliger and externally fertilizing Sebastolobus sp., both in the family Scorpaenidae. Despite the different reproductive behavior of these two closely related rockfish species, in both instances the SNBP consists of protamines. However, there is a significant increase in the arginine content of the protamine in the internally fertilizing rockfish. The relevance of this observation is discussed within the context of the P-type SNBP in teleosts. The rapid evolution of teleost protamines, including those in rockfish, has also allowed us to obtain a molecular phylogeny for this group of bony fish that is almost indistinguishable from that currently available from the use of conventional anatomical/paleontological markers.

Amino Acid Sequence↗

PubMed1993

Human male infertility may be due to a decrease of the protamine P2 content in sperm chromatin.

Basic chromosomal proteins were extracted from the sperm of fertile and infertile human males. The relative proportions of protamine 1, 2, and 3 were determined by scanning microdensitometry following electrophoresis of total protamine in polyacrylamide gels. The findings were as follows: (1) The proportion of protamine P(2 + 3) in sperm obtained from infertile males was lower than that in fertile males. (2) Protamine P(2 + 3) in infertile human males showed reduced affinity to DNA. The possibility that some cases of human male infertility may be due to mutation within the protamine P2 gene is discussed.

Chromatin↗

PubMed2006

Protamine: a unique and potent inhibitor of oligopeptidase B.

Oligopeptidase B is a serine endopeptidase found in prokaryotes, unicellular eukaryotes and higher plants. The enzyme has been shown recently to play a central role in the pathogenesis of several parasitic diseases such as African trypanosomiasis, and to be a potential therapeutic target. This study reports that protamine, a basic peptide rich in arginine, is a potent inhibitor at the nanomolar level of oligopeptidase B from E. coli and wheat. Protamines 1B, 2C, 3A and TP17 displayed similar inhibitory activities and were capable of binding strongly to oligopeptidase B without proteolytic cleavage. The concentration of protamine needed for 50% inhibition (IC50) of oligopeptidase B was 10(4)-fold lower than the IC50 of trypsin. Oligopeptidase B was highly sensitive to inhibition by protamines even in the presence of serum (IC50, 1 microM). These data indicate that protamines might provide information useful for the design of more specific synthetic oligopeptidase B inhibitors.

Enzyme Inhibitors↗

PubMed1996

A [+18RGD] protamine variant for nontoxic and effective reversal of conventional heparin and low-molecular-weight heparin anticoagulation.

Protamine sulfate reversal of heparin anticoagulation causes adverse side effects. Additionally, protamine sulfate is relatively ineffective at reversing factor Xa inhibition caused by low-molecular weight heparin (LMWH, Enoxaparin). Previously, a +18 compound partially reversed heparin and LMWH with minimal toxicity. In the present study, a new +18 protamine-like variant, [+18RGD], with an added RGD sequence [acetyl-EA(R2A2R2A)4R2GRGDSPA-amide], was compared to a previously developed compound, [+18BE,Acetyl-EAA-(K2A2K2A)4K2-Amide] and standard protamine [Prot +21] regarding the reversal of conventional unfractionated heparin (Hep) and LMWH. These three agents were given at 1 mg per 100 IU activity of Hep or LMWH rapidly over 10 sec. Hemodynamic toxicity was based on maximum declines in blood pressure, heart rate, cardiac output, and oxygen consumption over the first 5 min after reversal (calculated as a total toxicity score, TTS). The more negative the TTS, the more toxic the agent. Degrees of toxicity (TTS) of [+18RGD], [+18BE],and[Prot +21] for reversal of Hep were -1.19, -2.00, and -7.32, respectively; and for reversal of LMWH they were -2.85, -3.98,and -6.17, respectively. These differences were significant for Hep (P < 0.01) and approached significance for LMWH (P = 0.07). Maximum hemodynamic perturbations paralleled the TTS pattern. [+18RGD] provided equal reversal efficacy to [Prot +21] for Hep, with a statistically significant (P < 0.05) lessening of platelet count declines (Plt 27, -46, and -55%, respectively). [+18RGD] improved reversal efficacy for LMWH, at 3, 10, and 30 min following its administration. At 3 min, antifactor Xa reversal was 72, 40, and 30%, respectively, for [+18RGD], [+18BE], and [Prot +21]; [+18RGD] effects were significantly better (P < 0.01). [+18RGD] reversed both Hep and LMWH anticoagulation with minimal toxicity. Such a compound should decrease clinical complications attending the use of standard protamine for reversal of conventional heparin or LMWH anticoagulation.

Amino Acid Sequence↗

PubMed1995

Sequence analysis and structural features of the largest known protamine isolated from the sperm of the archaeogastropod Monodonta turbinata.

Protamine of the archaeogastropod mollusc Monodonta turbinata has been isolated and characterized. With a mass of 13,476 Da, it is the largest known protamine. Amino acid sequence of this protamine (106 residues) was established from data provided by automated sequence analysis and mass spectrometry of the protein and of its fragments. The primary structure of the NH2-terminal region exhibits repetitive sequence motifs "Basic-Ser" (mainly R-S) and both central and COOH-terminal regions are composed by arginine clusters. The amino acid sequence of Monodonta turbinata protamine shows structural similarities with other protamines from invertebrates and from birds and mammals.

Amino Acid Sequence↗

PubMed1990

Chromosomal localization of the human protamine genes, PRM1 and PRM2, to 16p13.3 by in situ hybridization.

Protamines are sperm-specific proteins that replace histones in the nuclear chromatin of mature spermatozoa. A chromosomal localization of the genes coding for human protamines has been achieved by in situ hybridization. Two cDNA probes of 423 bp and 397 bp containing the entire coding sequence for human protamine 1 (HP1) and human protamine 2 (HP2), respectively, have been used. The genes, called PRM1 and PRM2, have been found, tightly linked, on band 16p13.3. Arguments are given for the existence of these two genes as single copies, PRM1 coding for the unique HP1 protamine and PRM2 coding for a precursor of several proteins belonging to the HP2 family.

Chromosome Banding↗

PubMed1993

Glutamate enhances brain damage and albumin content in cerebrospinal fluid after intracarotid protamine infusion.

The blood-brain barrier was opened by intracarotid infusion of 5 mg protamine sulfate in 100 microliters 0.9% NaCl over a period of 30 s either alone or followed by infusion of 10 mg L-glutamate in 0.9% NaCl. Glutamate alone was infused in four control rats. Cisternal cerebrospinal fluid (CSF) was withdrawn before protamine administration and before the brains were fixed in situ 1, 24 or 72 h later. The albumin extravasation and glial reactivity was evaluated by immunohistochemistry on paraffin sections. The CSF albumin was significantly increased in both the protamine and protamine/glutamate groups but remained high at 24 and 72 h in the protamine/glutamate group only. Spongiotic lesions with shrunken nerve cells were observed 1 and 24 h after infusion of protamine alone or in combination with glutamate. Whereas such changes were not seen 72 h after protamine infusion, they remained and had progressed at 72 h in the protamine/glutamate group, indicating that glutamate induces delayed cellular damage when given access to the brain through an altered blood-brain barrier.

Animals↗

PubMed1979

Replacement of protamine by F1 histone during reactivation of fused human sperm nuclei.

Rabbit antisera, specific for the histones F1, F2a2, F2b, F3 and for protamine were used to monitor a possible transition from protamine towards somatic-type histones during sperm nucleus reactivation, following human sperm fusion with mouse fibroblasts. Mature human sperm nuclei were shown to contain the histones F2a2, F2b, F3 and protamine, but were missing F1 histone by immuno cytochemistry using the indirect fluorescence method. However, a gradual disappearance of protamine from fused sperm nuclei, could be observed during the first 24 h of reactivation. Subsequently, F1 histone could be detected in increasing concentrations in 60% of reactivated sperm nuclei, during the next four days. The shift from protamine towards F1 histone could also be visualized cytochemically via staining with brilliant sulphaflavine, which appears to discriminate between sperm nuclei on the basis of their F1 histone content.

Animals↗

PubMed1984

Isolation and in vitro translation of a mammalian protamine mRNA.

mRNA was isolated from sexually mature rat, rabbit, and bovine testes. Poly(A+) and (A-) RNAs were prepared and hybridized to a rainbow-trout protamine probe. The bovine (A+) fraction showed significant hybridization compared to the other species and these related sequences were also found in total bovine DNA. Bovine mRNA programmed the in vitro synthesis of a basic protein that possessed protamine-like properties. The mRNA was fractionated by agarose-gel electrophoresis and the fractions hybridized to the trout protamine probe. A significant hybridization signal was observed corresponding to a mRNA of approximately 400 nucleotides in length which coded for the protamine-like protein. The data support the view that we have isolated a mammalian (bovine) protamine mRNA.

Animals↗

PubMed1988

Aberrant protamine 1/protamine 2 ratios in sperm of infertile human males.

Protamines were extracted from the sperm of fertile and infertile human males and the relative proportion of protamines 1, 2, and 3 were determined by scanning microdensitometry following electrophoresis of total protamine in polyacrylamide gels. The proportion of the three protamines was found to be similar in sperm obtained from different normal males. The distribution of protamines in sperm obtained from a select group of infertile males producing an elevated level of large sperm heads, in contrast, was different from that of the fertile males.

Densitometry↗

PubMed1989

Effects of protamine on histamine release from human lung.

Animal mast cell models demonstrate direct histamine release by protamine. Investigators have proposed that protamine also releases histamine in man. We studied the effects of protamine alone and heparin-protamine mixtures on minced lung tissue for evidence of histamine release. We were unable to demonstrate the release of histamine despite positive anti-IgE controls. Nonimmunologic histamine release from human lung appears unlikely as a mechanism for protamine reactions in man.

Antibodies, Anti-Idiotypic↗

PubMed1988

Sequence similarities of the protamine genes: implications for regulation and evolution.

With the recent availability of the primary structural data for the trout, bovine, and mouse protamine genes, a detailed comparison of their structures has been made. This has revealed extensive conservation of potentially biologically significant regions. An inverse correlation is apparent between gene copy number and the number of sequence-distinct protamines synthesized with the number of CP-box-like (CCYPCCC) putative transcription modulating sequences situated 5' to these genes. A common nucleotide sequence 5' to the CP-box-like putative transcription modulating sequence(s) at the end of a common region has been identified. It is postulated that this is the testis-specific protamine P1 transcription regulator sequence. Evidence based on sequence similarity is also provided for the existence of a primordial protamine gene and a scheme for the evolution of vertebrate protamine genes is proposed.

Amino Acid Sequence↗

PubMed1994

The beneficial effects of aminophylline administration on heparin reversal with protamine.

The aim of this study was to demonstrate the beneficial effects of aminophylline on protamine cardiotoxicity. Thirty-four patients were examined, 17 of whom received aminophylline 3 mg/kg before protamine administration, being the study group, while the other 17, being the control group, did not. All cardiac output and biochemical measurements were evaluated 5 min following protamine administration. The cAMP level was 43.4 +/- 3.51 pmol/ml in the study group and 18.7 +/- 2.98 in the control group (P < 0.0001) before protamine administration, while the oxygen extraction rate decreased from 49% to 44 +/- 2% in the control group, and from 51.2% to 47 +/- 3% in the study group (P < 0.03). The N-acetyl glucosaminidase value was 16.9 +/- 13.9 pmol/ml in the study group and 27.8 +/- 1.47 pmol/ml in the control group (P < 0.01), and myocardial lactate extraction was -0.20 +/- 0.03 in the control group and -0.07 +/- 0.07 in the study group (P < 0.001). The left ventricular stroke work index was 28.6 +/- 3.14 gm/m2 in the control group and 37 +/- 6.77 gm/m2 in the study group (P < 0.002). The findings of this study led us to conclude that the adverse effects of heparin neutralization using protamine can be relieved by aminophylline.

Acetylglucosaminidase↗

PubMed1984

Cardiac arrest following protamine administration.

A case report of fatal cardiac arrest following protamine reversal of systemic heparinization during vascular surgery is presented. Patients who have received protamine zinc insulin, NPH insulin, and those with previous exposure to protamine sulphate or allergy to fish are more likely to have a reaction to protamine. Protamine-induced hypotension can be mediated by immunological or non-immunological mechanisms. Several alternative methods of heparin reversal which may avoid similar catastrophes are presented.

Anaphylaxis↗

PubMed2004

Protamine enhances uptake of cationic liposomes in angiogenic microvessels.

INTRODUCTION: Cationic liposomes have been shown to target angiogenic endothelial cells of solid tumours. Supposing a charge-related mechanism might be responsible for liposome-endothelial interaction, we investigated the effect of intravenous pre-injection of the charged molecules protamine, a polycationic protein, and fucoidan, a polyanionic polysaccharide on the accumulation of cationic liposomes within the blood vessels of a solid tumour. MATERIALS AND METHODS: Experiments were performed using the amelanotic hamster melanoma A-Mel-3 growing in a dorsal skinfold chamber of hamsters. Accumulation of fluorescently-labelled cationic liposomes was quantified by intravital macroscopy and digital image analysis of tumour (t) and surrounding normal host tissue (n) over an observation period of 6 h. All animals received an i.v. injection of cationic liposomes. Animals of the control group were pre-treated with an i.v. injection of 0.9% saline, while animals of group 2 received positively charged protamine and animals of group 3 negatively charged fucoidan prior to liposome injection. RESULTS: In control animals i.v. injection of cationic liposomes revealed a preferential targeting of the tumour vessels, indicated by a maximal t/n ratio of 2.2 +/- 0.24 and a maximal fluorescence intensity (fmax) corresponding to the tumour of 66 +/- 12 [% standard]. While there were no significant differences of liposome accumulation within normal host tissue, accumulation of cationic liposomes within the tumour was significantly enhanced after the pre-administration of protamine (fmax: 117 +/- 12 [% standard]). The t/n ratio was significantly increased in protamine pre-treated animals (5.3 +/- 1.7) in comparison to control and fucoidan treated animals. In contrast, pre-injection of fucoidan resulted in reduced maximal fluorescence intensities in tumour (47 +/- 8 [% standard]) and normal surrounding host tissue. CONCLUSION: Pre-administration of protamine increases the accumulation of cationic liposomes in a solid tumour animal model causing an increased selectivity of cationic liposomes in targeting angiogenic microvessels.

Animals↗

PubMed1976

The heterogeneity of the protamines from human spermatozoa.

Nuclear basic protein from ejaculated human spermatozoa were labelled with iodo[14C1]acetic acid and fractionated by ion-exchange chromatography into several pools (named A-K). Gel electrophoresis indicated that the minor protamine components, were present in pool D and that, of the major protamine components, component 1 (pools E, F, G, H) was well separated from the unresolved mixture of component 2 and component 3 (pools I, J, K). Pools G and J were free of other contaminants. Pools D, G, and J produced different radioactive peptides on digestion with trypsin and with thermolysin, and also had quite distinct amino acid compositions. This suggests that the heterogeneity of human protamines is caused by differences in amino acid sequence. Major component 1 also seems to be heterogenous, since it was found in two distinct peaks (pools E and G), but post-translational modification as a cause of the two types of component 1 has not been ruled out. Although all the human protamine components are similar to other mammalian protamines in containing half-cysteine and tyrosine, they also have unique common features such as high histidine and high glutamic acid contents.

Amino Acids↗

PubMed1990

Inactivation of bovine kidney cytosolic protamine kinase by the catalytic subunit of protein phosphatase 2A.

Incubation of highly purified preparations of the bovine kidney cytosolic protamine kinase in the presence of near homogeneous preparations of the catalytic subunit of protein phosphatase 2A (PrP2Ac) from bovine kidney resulted in time-dependent inactivation of the protamine kinase. By contrast, incubation of bovine kidney cytosolic casein kinase II with PrP2Ac had no effect on the activity of this casein kinase II. In the presence of 10 mM sodium fluoride, 10 mM inorganic orthophosphate, 1 mM pyrophosphate or 0.1 mM ATP, the inactivation of the protamine kinase by PrP2Ac was completely inhibited. Half-maximal inhibition by ATP occurred at about 20 microM. The rate of inactivation of the protamine kinase by PrP2Ac was unaffected by Mg2+, Mn2+, Ca2+, EDTA or EGTA at 1 mM. The results strongly indicate that the activity of the cytosolic protamine kinase is regulated by phosphorylation/dephosphorylation.

Adenosine Triphosphate↗