a simple protein found in fish sperm; rich in arginine; simpler in composition than globulin or albumin; counteracts the anticoagulant effect of heparin
Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in the spermatozoon than histones, but they must be decompressed before the genetic data can be used for protein synthesis. However, in humans and maybe other primates, 10-15% of the sperm's genome is packaged by histones thought to bind genes that are essential for early embryonic development.[1]
Contents
1Spermatogenesis
2Medical uses
3Examples
3.1Human
3.2Fish
4Protamine structure
5References
6External links
Spermatogenesis
During the formation of sperm, protamine binds to the phosphate backbone of DNA using the arginine-rich domain as an anchor. DNA is then folded into a toroid, an O-shaped structure, although the mechanism is not known. A sperm cell can contain up to 50,000 toroid-shaped structures in its nucleus with each toroid containing about 50 kilobases.[2] Before the toroid is formed, histones are removed from the DNA by transition nuclear proteins, so that protamine can condense it. The effects of this change are 1) an increase in sperm hydrodynamics for better flow through liquids by reducing the head size 2) decrease in the occurrence of DNA damage 3) removal of the epigenetic markers that occur with histone modifications.[3]
The structure of the sperm head is also related to protamine levels. The ratio of protamine 2 to protamine 1 and transition nuclear proteins has been found to change the sperm head shape in various species of mice, by altering the expression of protamine 2 via mutations in its promoter region. A decrease in the ratio has been found to increase the competitive ability of sperm in Mus species. However, further testing is required to determine how this ratio influences the shape of the head and whether monogamy influences this selection. In humans, studies show that men who have unbalanced Prm1/Prm2 are subfertile or infertile.[4]
Medical uses
When mixed with insulin, protamines slow down the onset and increase the duration of insulin action (see NPH insulin).[5]
Protamine is used in cardiac surgery, vascular surgery, and interventional radiology procedures to neutralize the anti-clotting effects of heparin. Adverse effects include increased pulmonary artery pressure and decrease peripheral blood pressure, myocardial oxygen consumption, cardiac output, and heart rate.[6]
Protamine sulfate is an antidote for heparin overdose.[7] A chain shortened version of protamine also acts as a potent heparin antagonist, but with markedly reduced antigenicity.[8]
In gene therapy, protamine sulfate's ability to condense plasmid DNA along with its approval by the U.S. Food and Drug Administration (FDA) have made it an appealing candidate to increase transduction rates by both viral[9] and nonviral (e.g. utilizing cationic liposomes)[10] mediated delivery mechanisms.
Protamine may be used as a drug to prevent obesity. Protamine has been shown to deter increases in body weight and low-density lipoprotein in high-fat diet rats. This effect occurs through the inhibition of lipase activity, an enzyme responsible for triacylglycerol digestion and absorption, resulting in a decrease in the absorption of dietary fat. No liver damage was found when the rats were treated with protamine. However, emulsification of long-chain fatty acids for digestion and absorption in the small intestine is less constant in humans than rats, which will vary the effectiveness of protamine as a drug. Furthermore, human peptidases may degrade protamine at different rates, thus further tests are required to determine protamine’s ability to prevent obesity in humans.[11]
Examples
Mice, humans[1] and certain fish have two or more different protamines, whereas the sperm of bull and boar,[12] have one form of protamine due to a mutation in the PRM2 gene. In the rat, although the gene for PRM2 is present, expression of this protein is extremely small because of limited transcription due to an inefficient promoter in addition to altered processing of the mRNA transcript.[13]
Human
The 2 human protamines are denoted PRM1 and PRM2.
Fish
Examples of protamines from fish are:
salmine from salmon
clupeine from herring sperm (Clupea)
iridine from rainbow trout
thinnine from tunafish (Thunnus)
stelline from starry sturgeon (Acipenser stellatus)
scylliorhinine from dogfish (Scylliorhinus)
Protamine structure
The primary structure of protamine P1, the protamine used for packaging DNA in sperm cells, in placental mammals is usually 49 or 50 amino acids long. This sequence is divided into three separate domains: an arginine-rich domain for DNA binding flanked by shorter peptide sequences containing mostly cysteine residues. The arginine-rich domain consists of 3-11 arginine residues and is conserved between fish protamine and mammalian protamine 1 sequences at about 60-80% sequence identity.[1]
After translation, the protamine P1 structure is immediately phosphorylated at all three of the above-mentioned domains. Another round of phosphorylation occurs when the sperm enters the egg, but the function of these phosphorylations is uncertain. When protamine P1 binds to DNA, cysteine from the amino terminal of one protamine P1 forms disulfide bonds with the cysteine from the carboxy-terminal of another protamine P1. The disulfide bonds function to prevent the dissociation of protamine P1 from DNA until the bonds are reduced when the sperm enters the egg.[1]
The secondary and tertiary structure of protamine is not known with certainty, but several proposals have been published.[14][15][16]
References
^ abcdBalhorn R (2007). "The protamine family of sperm nuclear proteins". Genome Biology. 8 (9): 227. doi:10.1186/gb-2007-8-9-227. PMC 2375014. PMID 17903313.
^Brewer LR, Corzett M, Balhorn R (Oct 1999). "Protamine-induced condensation and decondensation of the same DNA molecule". Science. 286 (5437): 120–3. doi:10.1126/science.286.5437.120. PMID 10506559.
^Woop M (January 2015). "Optimizing Tethered Particle Motion to Measure DNA Compaction by Protamine". Biophysical Journal. 108: 393a. doi:10.1016/j.bpj.2014.11.2156.
^Lüke L, Campbell P, Varea Sánchez M, Nachman MW, Roldan ER (May 2014). "Sexual selection on protamine and transition nuclear protein expression in mouse species". Proceedings of the Royal Society B: Biological Sciences. 281 (1783): 20133359. doi:10.1098/rspb.2013.3359. PMC 3996607. PMID 24671975.
^Owens DR (Jun 2011). "Insulin preparations with prolonged effect". Diabetes Technology & Therapeutics. 13 Suppl 1: S5–14. doi:10.1089/dia.2011.0068. PMID 21668337.
^Carr JA, Silverman N (Oct 1999). "The heparin-protamine interaction. A review". The Journal of Cardiovascular Surgery. 40 (5): 659–66. PMID 10596998.
^Weiler JM, Freiman P, Sharath MD, Metzger WJ, Smith JM, Richerson HB, Ballas ZK, Halverson PC, Shulan DJ, Matsuo S (Feb 1985). "Serious adverse reactions to protamine sulfate: are alternatives needed?". The Journal of Allergy and Clinical Immunology. 75 (2): 297–303. doi:10.1016/0091-6749(85)90061-2. PMID 2857186.
^Byun Y, Chang LC, Lee LM, Han IS, Singh VK, Yang VC (2000). "Low molecular weight protamine: a potent but nontoxic antagonist to heparin/low molecular weight protamine". ASAIO Journal. 46 (4): 435–9. doi:10.1097/00002480-200007000-00013. PMID 10926141.
^Cornetta K, Anderson WF (Feb 1989). "Protamine sulfate as an effective alternative to polybrene in retroviral-mediated gene-transfer: implications for human gene therapy". Journal of Virological Methods. 23 (2): 187–94. doi:10.1016/0166-0934(89)90132-8. PMID 2786000.
^Duarte-Vázquez MA, García-Padilla S, Olvera-Ochoa L, González-Romero KE, Acosta-Iñiguez J, De la Cruz-Cordero R, Rosado JL (Jun 2009). "Effect of protamine in obesity induced by high-fat diets in rats". International Journal of Obesity. 33 (6): 687–92. doi:10.1038/ijo.2009.78. PMID 19434066.
^Maier WM, Nussbaum G, Domenjoud L, Klemm U, Engel W (Mar 1990). "The lack of protamine 2 (P2) in boar and bull spermatozoa is due to mutations within the P2 gene". Nucleic Acids Research. 18 (5): 1249–54. doi:10.1093/nar/18.5.1249. PMC 330441. PMID 2320417.
^Bunick D, Balhorn R, Stanker LH, Hecht NB (May 1990). "Expression of the rat protamine 2 gene is suppressed at the level of transcription and translation". Experimental Cell Research. 188 (1): 147–52. doi:10.1016/0014-4827(90)90290-q. PMID 2328773.
^Martins RP, Ostermeier GC, Krawetz SA (Dec 2004). "Nuclear matrix interactions at the human protamine domain: a working model of potentiation". The Journal of Biological Chemistry. 279 (50): 51862–8. doi:10.1074/jbc.M409415200. PMID 15452126.
^Vilfan ID, Conwell CC, Hud NV (May 2004). "Formation of native-like mammalian sperm cell chromatin with folded bull protamine". The Journal of Biological Chemistry. 279 (19): 20088–95. doi:10.1074/jbc.M312777200. PMID 14990583.
^Biegeleisen K (Aug 2006). "The probable structure of the protamine-DNA complex". Journal of Theoretical Biology. 241 (3): 533–40. doi:10.1016/j.jtbi.2005.12.015. PMID 16442565.
External links
Protamines at the US National Library of Medicine Medical Subject Headings (MeSH)
V03AB14 (WHO)
v
t
e
Antidotes (V03AB)
Nervous system
Nerve agent / Organophosphate poisoning
Atropine#
Biperiden
Diazepam#
Oximes
Obidoxime
Pralidoxime
see also: Cholinesterase
Barbiturate overdose
Bemegride
Ethamivan
Benzodiazepine overdose
Cyprodenate
Flumazenil
GHB overdose
Physostigmine
SCH-50911
Opioid overdose
Diprenorphine
Doxapram
Nalmefene
Nalorphine
Naloxone#
Naltrexone
Reversal of neuromuscular blockade
Sugammadex
Circulatory system
Beta blocker
Glucagon
Digoxin toxicity
Digoxin Immune Fab
Heparin
Protamine#
Other
Arsenic poisoning
Dimercaprol#
Succimer
Cyanide poisoning
4-Dimethylaminophenol
Hydroxocobalamin
nitrite
Amyl nitrite
Sodium nitrite#
Sodium thiosulfate#
Hydrofluoric acid
Calcium gluconate#
Methanol / Ethylene glycol poisoning
Primary alcohols: Ethanol
Fomepizole
Paracetamol toxicity (Acetaminophen)
Acetylcysteine#
Glutathione
Methionine#
Toxic metals (cadmium
lead
mercury
thallium)
Dimercaprol#
Edetates
Prussian blue#
Other
iodine-131
Potassium iodide
Methylthioninium chloride#
oxidizing agent
Potassium permanganate
Prednisolone/promethazine
Emetic
Copper sulfate
Ipecacuanha
Syrup of ipecac
#WHO-EM
‡Withdrawn from market
Clinical trials:
†Phase III
§Never to phase III
UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
5. 冠動脈バイパス術の心臓以外の早期合併症 early noncardiac complications of coronary artery bypass graft surgery
English Journal
A ratiometric fluorescent quantum dots based biosensor for organophosphorus pesticides detection by inner-filter effect.
Yan X1, Li H2, Han X3, Su X4.
Biosensors & bioelectronics.Biosens Bioelectron.2015 Dec 15;74:277-83. doi: 10.1016/j.bios.2015.06.020. Epub 2015 Jun 20.
In this work, we develop a novel and sensitive sensor for the detection of organophosphorus pesticides based on the inner-filter effect (IFE) between gold nanoparticles (AuNPs) and ratiometric fluorescent quantum dots (RF-QDs). The RF-QDs has been designed by hybridizing two differently colored CdTe
Protamine-stabilized RNA as an ex vivo stimulant of primary human dendritic cell subsets.
Sköld AE1,2, van Beek JJ1, Sittig SP1, Bakdash G1, Tel J1, Schreibelt G1, de Vries IJ3,4.
Cancer immunology, immunotherapy : CII.Cancer Immunol Immunother.2015 Nov;64(11):1461-73. doi: 10.1007/s00262-015-1746-9. Epub 2015 Aug 15.
Dendritic cells (DCs) are key in connecting innate and adaptive immunity. Their potential in inducing specific immune responses has made them interesting targets for immunotherapeutic approaches. Our research group was the first to exploit the naturally occurring myeloid DCs (mDCs) and plasmacytoid
Prothrombotic SERPINC1 Gene Polymorphism may Affect Heparin Sensitivity Among Different Ethnicities of Chinese Patients Receiving Heart Surgery.
Wang J1, Ma HP1, Ti AL1, Zhang YQ1, Zheng H2.
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.Clin Appl Thromb Hemost.2015 Nov;21(8):760-7. doi: 10.1177/1076029614556744. Epub 2014 Oct 30.
The purpose of this study was to investigate a possible correlation between single-nucleotide polymorphisms (SNPs) of the antithrombin (gene, SERPINC1, and perioperative sensitivity to heparin in patients receiving heart surgery. The SERPINC1 genotype and allele frequency, coagulation parameters 24
Periprocedural Anticoagulation of Patients Undergoing Pericardiocentesis for Cardiac Tamponade Complicating Catheter Ablation of Atrial Fibrillation
Lin Tao,Bai Rong,Chen Ying-wei,Yu Rong-hui,Tang Ri-bo,Sang Cai-hua,Li Song-nan,Ma Chang-sheng,Dong Jian-zeng
International Heart Journal 56(1), 56-61, 2015
… Protamine sulfate was administered to neutralize heparin (1 mg neutralizes 100 units heparin) in 11 patients with persistent pericardial bleeding and vitamin K1 (10 mg) was given to reverse warfarin in 3 patients with supratherapeutic INR (INR > …
The Pro-Healing Effect of Protamine-Hydrolysate Peptides on Skin Wounds Involves TGF-β/Smad Signaling
K. Bhawal Ujjal,Lee Hye-jin,Uchida Ryoichiro,Okumura Shigetoshi,Harayama Shuichiro,Eguchi Yawara,Fukumoto Masahiko,Kuboyama Noboru
Journal of Hard Tissue Biology 24(1), 91-98, 2015
… This study characterized the molecular mechanisms of the effects of protamine-hydrolysate peptides (p-h peptides) on skin wound healing in rats by analyzing the transforming growth factor (TGF)-β signaling pathway. …
