Summary: A group of simple proteins that yield basic amino acids on hydrolysis and that occur combined with nucleic acid in the sperm of fish. Protamines contain very few kinds of amino acids. Protamine sulfate combines with heparin to form a stable inactive complex; it is used to neutralize the anticoagulant action of heparin in the treatment of heparin overdose. (From Merck Index, 11th ed; Martindale, The Extra Pharmacopoeia, 30th ed, p692)

Top Publications

  1. Reynolds F, Weissleder R, Josephson L. Protamine as an efficient membrane-translocating peptide. Bioconjug Chem. 2005;16:1240-5 pubmed
    ..was reacted with the N-hydroxysuccinimide ester of tetramethylrhodamine to yield tetramethylrhodamine-labeled protamines (Pro(Rh)) containing one mole of fluorochrome per mole of protein...
  2. Popłońska K, Kwiatkowska M, Wojtczak A, Polit J. Immunogold evidence suggests that endoplasmic reticulum is the site of protamine-type protein synthesis and participates in translocation of these proteins into the nucleus during Chara vulgaris spermiogenesis. Biol Reprod. 2009;80:572-80 pubmed publisher
    ..The above results correspond with those of other authors showing that in animals, protamines bind with lamin B receptors localized in the inner membrane of the nuclear envelope...
  3. Dai L, Tsai Morris C, Sato H, Villar J, Kang J, Zhang J, et al. Testis-specific miRNA-469 up-regulated in gonadotropin-regulated testicular RNA helicase (GRTH/DDX25)-null mice silences transition protein 2 and protamine 2 messages at sites within coding region: implications of its role in germ cell development. J Biol Chem. 2011;286:44306-18 pubmed publisher
    ..Collectively, these studies indicate that GRTH, a multifunctional RNA helicase, acts as a negative regulator of miRNA-469 biogenesis and consequently their function during spermatogenesis. ..
  4. Yuan H, Zhang W, Du Y, Hu F. Ternary nanoparticles of anionic lipid nanoparticles/protamine/DNA for gene delivery. Int J Pharm. 2010;392:224-31 pubmed publisher
    ..Lipid nanoparticles with 20 wt% OA/protamine/DNA ternary nanoparticles (w/w/w, 65:6:3) showed the best and the most durable gene transfection even in the presence of serum. ..
  5. Vighi E, Montanari M, Ruozi B, Tosi G, Magli A, Leo E. Nuclear localization of cationic solid lipid nanoparticles containing Protamine as transfection promoter. Eur J Pharm Biopharm. 2010;76:384-93 pubmed publisher
  6. Rathke C, Barckmann B, Burkhard S, Jayaramaiah Raja S, Roote J, Renkawitz Pohl R. Distinct functions of Mst77F and protamines in nuclear shaping and chromatin condensation during Drosophila spermiogenesis. Eur J Cell Biol. 2010;89:326-38 pubmed publisher
    ..These data support the long-standing hypothesis that the switch from a histone- to protamine-based chromatin protects the paternal genome from mutagens. ..
  7. Arbab A, Janic B, Knight R, Anderson S, Pawelczyk E, Rad A, et al. Detection of migration of locally implanted AC133+ stem cells by cellular magnetic resonance imaging with histological findings. FASEB J. 2008;22:3234-46 pubmed publisher
    ..HIF-1alpha was expressed at both the periphery and central parts of the tumor. This work demonstrates that magnetically labeled cells can be used as probes for MRI and histological identification of administered cells. ..
  8. Sadek H, Latif S, Collins R, Garry M, Garry D. Use of ferumoxides for stem cell labeling. Regen Med. 2008;3:807-16 pubmed publisher
    ..The ferumoxide-protamine sulfate combination can be used safely and effectively to enhance the detection and isolation of cardiogenic stem cell populations. ..
  9. Liu J, Guo S, Li Z, Liu L, Gu J. Synthesis and characterization of stearyl protamine and investigation of their complexes with DNA for gene delivery. Colloids Surf B Biointerfaces. 2009;73:36-41 pubmed publisher
    ..A possible mechanism is proposed for the formation of complex of SP/DNA. The SP also shows a low cytotoxicity similar to protamine. ..

More Information


  1. van Buul G, Farrell E, Kops N, van Tiel S, Bos P, Weinans H, et al. Ferumoxides-protamine sulfate is more effective than ferucarbotran for cell labeling: implications for clinically applicable cell tracking using MRI. Contrast Media Mol Imaging. 2009;4:230-6 pubmed publisher
    ..Consequently, hBMSC and chondrocyte labeling with ferumoxides-protamine is more effective and results in more specific cell labeling than ferucarbotran. ..
  2. Parodi G, Migliorini A, Valenti R, Bellandi B, Signorini U, Moschi G, et al. Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial). Am J Cardiol. 2010;105:1053-9 pubmed publisher
    ..In conclusion, in percutaneous coronary intervention patients pretreated with clopidogrel and aspirin, bivalirudin was associated with less major bleeding and fewer ischemic complications and a better net clinical outcome than UFH. ..
  3. Chen J, Yu Z, Chen H, Gao J, Liang W. Transfection efficiency and intracellular fate of polycation liposomes combined with protamine. Biomaterials. 2011;32:1412-8 pubmed publisher
    ..The addition of protamine, containing nuclear localization signals, improved nuclear entry of DNA. The internalization pathways for PCLs involved multiple processes and were possibly dependent on cell lines. ..
  4. Chang Y, Lee Chang J, Imam J, Buddavarapu K, Subaran S, Sinha Hikim A, et al. Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation. Proc Natl Acad Sci U S A. 2012;109:5750-5 pubmed publisher
  5. Thu M, Bryant L, Coppola T, Jordan E, Budde M, Lewis B, et al. Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging. Nat Med. 2012;18:463-7 pubmed publisher
    ..In vivo MRI detected 1,000 HPF-labeled cells implanted in rat brains. This HPF labeling method should facilitate the monitoring by MRI of infused or implanted cells in clinical trials. ..
  6. Martínez Gómez J, Csaba N, Fischer S, Sichelstiel A, Kundig T, Gander B, et al. Surface coating of PLGA microparticles with protamine enhances their immunological performance through facilitated phagocytosis. J Control Release. 2008;130:161-7 pubmed publisher
    ..These results open the way for further research into a novel technology that combines the use protamine for facilitated cell penetration of that and biodegradable microparticles for prolonged antigen or drug release. ..
  7. Simon L, Castillo J, Oliva R, Lewis S. Relationships between human sperm protamines, DNA damage and assisted reproduction outcomes. Reprod Biomed Online. 2011;23:724-34 pubmed publisher
    The exchange of histones with protamines in sperm DNA results in sperm chromatin compaction and protection. Variations in sperm protamine expression are associated with male infertility...
  8. Nybo M, Madsen J. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103:192-6 pubmed publisher
    ..Our study also emphasizes the need for critical appraisal of many routine procedures: in all aspects of medical care, systematic literature review conducted in a well-structured, repeated manner should be given high priority. ..
  9. Miller D, Brinkworth M, Iles D. Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction. 2010;139:287-301 pubmed publisher
    ..spermatozoa replace most of their histones with smaller, highly basic arginine and (in eutherians) cysteine rich protamines. One reason for such a high level of compaction is that it may help optimise nuclear shape and hence support the ..
  10. Nakamura S, Kanatani Y, Kishimoto S, Nakamura S, Ohno C, Horio T, et al. Controlled release of FGF-2 using fragmin/protamine microparticles and effect on neovascularization. J Biomed Mater Res A. 2009;91:814-23 pubmed publisher
    ..c) 2008 Wiley Periodicals, Inc. J Biomed Mater Res, 2009. ..
  11. Hecht N, Behr R, Hild A, Bergmann M, Weidner W, Steger K. The common marmoset (Callithrix jacchus) as a model for histone and protamine expression during human spermatogenesis. Hum Reprod. 2009;24:536-45 pubmed publisher
  12. DeRouchey J, Hoover B, Rau D. A comparison of DNA compaction by arginine and lysine peptides: a physical basis for arginine rich protamines. Biochemistry. 2013;52:3000-9 pubmed publisher
    b>Protamines are small, highly positively charged peptides used to package DNA at very high densities in sperm nuclei. Tight DNA packing is considered essential for the minimization of DNA damage by mutagens and reactive oxidizing species...
  13. Worawittayawong P, Leigh C, Weerachatyanukul W, Manochantr S, Sobhon P, Breed W, et al. Changes in distribution of basic nuclear proteins and chromatin organization during spermiogenesis in the greater bandicoot rat, Bandicota indica. Cell Tissue Res. 2008;334:135-44 pubmed publisher
    ..that transition proteins are present from step 7 spermatids and remain until the end of spermiogenesis, and that protamines appear at step 8...
  14. Kharidia R, Friedman K, Liang J. Improved gene expression using low molecular weight peptides produced from protamine sulfate. Biochemistry (Mosc). 2008;73:1162-8 pubmed
    ..Since LMWP peptides have low immunogenicity, they would be safer than protamine for use in gene therapies. ..
  15. Janic B, Rad A, Jordan E, Iskander A, Ali M, Varma N, et al. Optimization and validation of FePro cell labeling method. PLoS ONE. 2009;4:e5873 pubmed publisher
    ..The new technique with short incubation time using 100 microg/ml of Fe and 3 microg/ml of Pro is effective in labeling cells for cellular MRI. ..
  16. Golovko D, Henning T, Bauer J, Settles M, Frenzel T, Mayerhofer A, et al. Accelerated stem cell labeling with ferucarbotran and protamine. Eur Radiol. 2010;20:640-8 pubmed publisher
    ..Our results show internalization of ferucarbotran can be accelerated in MSCs with protamine, an approved heparin antagonist and potentially clinically applicable uptake-enhancing agent. ..
  17. Vighi E, Montanari M, Ruozi B, Iannuccelli V, Leo E. The role of protamine amount in the transfection performance of cationic SLN designed as a gene nanocarrier. Drug Deliv. 2012;19:1-10 pubmed publisher
    ..In conclusion, the amount of protamine as the transfection promoter in SLN affects not only the gene delivery ability of SLN but also their capacity to transfer genes efficiently to specific cell types...
  18. Garg P, Verma R, Cook L, Soofi A, Venkatareddy M, George B, et al. Actin-depolymerizing factor cofilin-1 is necessary in maintaining mature podocyte architecture. J Biol Chem. 2010;285:22676-88 pubmed publisher
    ..We conclude that cofilin-1 is necessary for maintenance of normal podocyte architecture and for actin structural changes that occur during induction and recovery from podocyte injury. ..
  19. Thomas J, Rekha M, Sharma C. Dextran-protamine polycation: an efficient nonviral and haemocompatible gene delivery system. Colloids Surf B Biointerfaces. 2010;81:195-205 pubmed publisher
    ..With the improved physicochemical, biological and transfection properties, Dex-P seems to be a promising gene delivery system. ..
  20. Prieto C, Saperas N, Arnan C, Hills M, Wang X, Chiva M, et al. Nucleoplasmin interaction with protamines. Involvement of the polyglutamic tract. Biochemistry. 2002;41:7802-10 pubmed
    ..However, although the stoichiometry with which protamines bind to these forms appears to be constant (2...
  21. Corzett M, Mazrimas J, Balhorn R. Protamine 1: protamine 2 stoichiometry in the sperm of eutherian mammals. Mol Reprod Dev. 2002;61:519-27 pubmed
    ..and high performance liquid chromatography (HPLC) were used to determine the content of the two protamines, and the identity of each protein was confirmed by amino-terminal sequencing or amino acid analysis...
  22. Liang J, Li Y, Song H, Park Y, Naik S, Yang V. ATTEMPTS: a heparin/protamine-based delivery system for enzyme drugs. J Control Release. 2002;78:67-79 pubmed
    ..Currently, modification of enzyme drugs has been optimized by recombinant DNA technology assisted by computer simulation. In addition, the original strategy has been revised to obtain enhanced therapeutic efficacy. ..
  23. Dadoune J. Expression of mammalian spermatozoal nucleoproteins. Microsc Res Tech. 2003;61:56-75 pubmed
    ..A number of biochemical events accompany the displacement of histones and the appearance of protamines in elongating spermatids...
  24. Shirley C, Hayashi S, Mounsey S, Yanagimachi R, Meistrich M. Abnormalities and reduced reproductive potential of sperm from Tnp1- and Tnp2-null double mutant mice. Biol Reprod. 2004;71:1220-9 pubmed
    ..Similarities between sperm defects found in Tnp mutants and infertile patients make the Tnp mutants a valuable tool with which to study outcomes following fertilization using sperm with compromised DNA integrity. ..
  25. Nasr Esfahani M, Salehi M, Razavi S, Mardani M, Bahramian H, Steger K, et al. Effect of protamine-2 deficiency on ICSI outcome. Reprod Biomed Online. 2004;9:652-8 pubmed
    During spermiogenesis, histones are replaced by protamines (P1 and P2), resulting in sperm chromatin condensation followed by a halt to gene expression in haploid spermatids and spermatozoa...
  26. Li L, Geng X, Yonkunas M, Su A, Densmore E, Tang P, et al. Ligand-dependent linkage of the ATP site to inhibition gate closure in the KATP channel. J Gen Physiol. 2005;126:285-99 pubmed
  27. Aoki V, Emery B, Liu L, Carrell D. Protamine levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl. 2006;27:890-8 pubmed
    ..The data also demonstrate individual sperm cells displaying the lowest protamine levels display diminished viability and increased sperm cell susceptibility to DNA damage. ..
  28. Pugsley M, Kalra V, Froebel Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle. Life Sci. 2002;72:293-305 pubmed
  29. Junghans M, Loitsch S, Steiniger S, Kreuter J, Zimmer A. Cationic lipid-protamine-DNA (LPD) complexes for delivery of antisense c-myc oligonucleotides. Eur J Pharm Biopharm. 2005;60:287-94 pubmed
    ..The C-MYC level was reduced after treatment of these antisense ODN carrier complexes. Furthermore, no changes in target mRNA concentration of the treated cells was found by reverse transcription and competitive multiplex-PCR. ..
  30. Ramos L, van der Heijden G, Derijck A, Berden J, Kremer J, van der Vlag J, et al. Incomplete nuclear transformation of human spermatozoa in oligo-astheno-teratospermia: characterization by indirect immunofluorescence of chromatin and thiol status. Hum Reprod. 2008;23:259-70 pubmed
    ..1/H3.2 isoform, histone TH2B, apoptosis-associated H4 acetylation (KM-2) and protamines. Subsequently, sperm samples were stained with the thiol-specific fluorochrome monobromobimane (mBBr) before and ..
  31. Pawelczyk E, Arbab A, Pandit S, Hu E, Frank J. Expression of transferrin receptor and ferritin following ferumoxides-protamine sulfate labeling of cells: implications for cellular magnetic resonance imaging. NMR Biomed. 2006;19:581-92 pubmed
    ..No changes in MTT and ROS analysis were noted. In conclusion, FE-Pro labeling elicited physiological changes of iron metabolism or storage, validating the safety of this procedure for cellular tracking by MRI. ..
  32. Pawelczyk E, Arbab A, Chaudhry A, Balakumaran A, Robey P, Frank J. In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: implications for cellular therapy. Stem Cells. 2008;26:1366-75 pubmed publisher
  33. Frehlick L, Eirín López J, Prado A, Su H, Kasinsky H, Ausio J. 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. J Exp Zool A Comp Exp Biol. 2006;305:277-87 pubmed
    ..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 ..
  34. Suganuma R, Yanagimachi R, Meistrich M. Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI. Hum Reprod. 2005;20:3101-8 pubmed
    ..The advantage of using caput epididymal sperm for ICSI in certain situations may be considered as an approach to be tested in human assisted reproduction. ..
  35. Arbab A, Yocum G, Rad A, Khakoo A, Fellowes V, Read E, et al. Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed. 2005;18:553-9 pubmed
    ..These data increase confidence that MRI studies of FePro-labeled HSC or MSC will provide an accurate representation of in vivo trafficking of unlabeled cells. ..
  36. Carrell D, Emery B, Hammoud S. Altered protamine expression and diminished spermatogenesis: what is the link?. Hum Reprod Update. 2007;13:313-27 pubmed
    ..human sperm chromatin undergoes a complex transition in which histones are extensively replaced by protamines in a carefully regulated transition including histone modifications and intermediate and temporary replacement ..
  37. Cho C, Jung Ha H, Willis W, Goulding E, Stein P, Xu Z, et al. Protamine 2 deficiency leads to sperm DNA damage and embryo death in mice. Biol Reprod. 2003;69:211-7 pubmed
    ..Although it is believed that protamines are essential for compaction of the sperm nucleus and to protect the DNA from damage, this has not been proven ..
  38. Lewis J, Song Y, de Jong M, Bagha S, Ausio J. A walk though vertebrate and invertebrate protamines. Chromosoma. 2003;111:473-82 pubmed
    An updated comparative analysis of protamines and their corresponding genes is presented, including representative organisms from each of the vertebrate classes and one invertebrate (squid, Loligo opalescens)...
  39. Wykes S, Krawetz S. Conservation of the PRM1 --> PRM2 --> TNP2 domain. DNA Seq. 2003;14:359-67 pubmed
    In mouse and human, the genes encoding protamines PRM1, PRM2 and transition protein TNP2 are found clustered together on chromosome 16...
  40. Piña Guzmán B, Solís Heredia M, Quintanilla Vega B. Diazinon alters sperm chromatin structure in mice by phosphorylating nuclear protamines. Toxicol Appl Pharmacol. 2005;202:189-98 pubmed
    ..Chemical alterations in sperm nuclear proteins (protamines), which pack DNA during the last steps of spermatogenesis, contribute to male reproductive toxicity...
  41. Aoki V, Liu L, Carrell D. Identification and evaluation of a novel sperm protamine abnormality in a population of infertile males. Hum Reprod. 2005;20:1298-306 pubmed
    ..We have identified a novel population of infertile males with a reduced P1/P2 ratio. Aberrant P1/P2 ratios arise from an abnormal concentration of P1 and/or P2, either of which is associated with male infertility. ..
  42. Aoki V, Moskovtsev S, Willis J, Liu L, Mullen J, Carrell D. DNA integrity is compromised in protamine-deficient human sperm. J Androl. 2005;26:741-8 pubmed
    The objective of this study was to examine the relationship between DNA integrity and protamines in human sperm. One hundred forty-nine male infertility patients were included in an Institutional Review Board-approved study...
  43. Cao C, Ding X, Ou Z, Liu C, Li P, Wang L, et al. In vivo transfection of NF-kappaB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats. Kidney Int. 2004;65:834-45 pubmed
    ..NF-kappaB decoy ODN treatment reduces the renal dysfunction and damage associated with ischemic ARF. Therefore, in vivo transfection of NF-kappaB decoy ODN provides a new therapeutic strategy for ischemic ARF. ..
  44. Wykes S, Krawetz S. The structural organization of sperm chromatin. J Biol Chem. 2003;278:29471-7 pubmed
    ..genome within the differentiating spermatid nucleus is facilitated by small basic nuclear proteins called protamines. Although the majority of the DNA in human sperm chromatin is bound by these proteins, a small percentage ..
  45. McLay D, Clarke H. Remodelling the paternal chromatin at fertilization in mammals. Reproduction. 2003;125:625-33 pubmed
    ..This morphological change is coincident with and likely dependent on the replacement of the sperm-specific protamines by oocyte-supplied histones and the organization of the chromatin into nucleosomes...
  46. van der Heijden G, Dieker J, Derijck A, Muller S, Berden J, Braat D, et al. Asymmetry in histone H3 variants and lysine methylation between paternal and maternal chromatin of the early mouse zygote. Mech Dev. 2005;122:1008-22 pubmed
    ..In summary the male, in contrast to female G1 chromatin, is uniform and contains predominantly histone H3.3 as histone H3 variant. ..
  47. Ducas J, Chan M, Miller A, Kashour T. Immediate protamine administration and sheath removal following percutaneous coronary intervention: a prospective study of 429 patients. Catheter Cardiovasc Interv. 2002;56:196-9 pubmed
    ..Follow-up at 30 days observed no deaths and only three target vessel revascularizations (0.7%). In conclusion, immediate reversal of anticoagulation and sheath removal after PCI is safe and feasible. ..
  48. Popłońska K. Cytochemical studies on histone-type and protamine-type proteins during spermiogenesis in Chara vulgaris and Chara tomentosa. Folia Histochem Cytobiol. 2002;40:233-4 pubmed
    ..VI-VIII) in two Charta species, while late spermiogenesis (st. IX) and mature spermatozoids (st. X) were characterised by the presence of protamine-like proteins only. ..
  49. Nasr Esfahani M, Razavi S, Mozdarani H, Mardani M, Azvagi H. Relationship between protamine deficiency with fertilization rate and incidence of sperm premature chromosomal condensation post-ICSI. Andrologia. 2004;36:95-100 pubmed
    ..05). A significant correlation was observed between sperm protamine deficiency with fertilization rate. Hence sperm protamine deficiency affects fertilization rate and possibly prones sperm to PCC post-ICSI. ..
  50. Dinauer N, Lochmann D, Demirhan I, Bouazzaoui A, Zimmer A, Chandra A, et al. Intracellular tracking of protamine/antisense oligonucleotide nanoparticles and their inhibitory effect on HIV-1 transactivation. J Control Release. 2004;96:497-507 pubmed
    ..In contrast, protamine/AS-PTO complexes were stable over 72 h, and failed to release AS-PTO. These results demonstrate that protamine/AS-ODN nanoparticles are useful for future therapeutical application to inhibit viral gene expression. ..
  51. Montet Abou K, Montet X, Weissleder R, Josephson L. Cell internalization of magnetic nanoparticles using transfection agents. Mol Imaging. 2007;6:1-9 pubmed
    ..Conditions for loading cells with Feridex and a TFA need to be carefully selected to minimize nanoparticle precipitation and dextran adsorption to the cell surface. ..
  52. Torregrosa N, Domínguez Fandos D, Camejo M, Shirley C, Meistrich M, Ballescà J, et al. Protamine 2 precursors, protamine 1/protamine 2 ratio, DNA integrity and other sperm parameters in infertile patients. Hum Reprod. 2006;21:2084-9 pubmed
    ..The positive correlation between TUNEL-positive sperm and pre-P2 at low pre-P2/P2 ratios also suggests a link between deficient protamine processing and decreased DNA integrity. ..
  53. Nasr Esfahani M, Salehi M, Razavi S, Anjomshoa M, Rozbahani S, Moulavi F, et al. Effect of sperm DNA damage and sperm protamine deficiency on fertilization and embryo development post-ICSI. Reprod Biomed Online. 2005;11:198-205 pubmed
    ..Unlike protamine deficiency, sperm DNA fragmentation does not preclude fertilization. Nonetheless, embryos derived from spermatozoa with high DNA damage have a lower potential to reach blastocyst stage. ..