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{{DrugProjectFormSinglePage
{{Pfam box |Symbol = Protamine_P1 |Name = Protamine P1 |Pfam = PF00260 |InterPro = IPR000221 |PROSITE = PDOC00047 |PDB = }}
|authorTag=
{{infobox protein
 
|Name=protamine 1
Gerald Chi
|caption=
 
|image=
<!--Overview-->
|width=
 
|HGNCid=9447
|genericName=
|Symbol=PRM1
 
|AltSymbols=
Protamine
|EntrezGene=5619
 
|OMIM=182880
|aOrAn=
|RefSeq=NM_002761
 
|UniProt=P04553
a
|PDB=
 
|ECnumber=
|drugClass=
|Chromosome=16
 
|Arm=p
[[heparin]] [[antagonist]]
|Band=13.13
 
|LocusSupplementaryData=
|indication=
}}
 
{{infobox protein
[[heparin]] [[overdose|overdosage]]
|Name=protamine 2
 
|caption=
|hasBlackBoxWarning=
|image=
 
|width=
Yes
|HGNCid=9448
 
|Symbol=PRM2
|adverseReactions=
|AltSymbols=
 
|EntrezGene=5620
[[flushing]], [[dyspnea]], [[nausea]], and [[vomiting]]
|OMIM=182890
 
|RefSeq=NM_002762
<!--Black Box Warning-->
|UniProt=P04554
 
|PDB=
|blackBoxWarningTitle=
|ECnumber=
BOXED WARNING
|Chromosome=16
 
|Arm=p
|blackBoxWarningBody=
|Band=13.13
 
|LocusSupplementaryData=
* Protamine sulfate can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension.  Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine, and current or previous use of protamine-containing drugs (NPH insulin, protamine zinc insulin, and certain beta-blockers).  Allergy to fish, previous vasectomy, and severe left ventricular dysfunction and abnormal preoperative pulmonary hemodynamics also may be risk factors.  In patients with any of these risk factors, the risk to benefit of administration of protamine sulfate should be carefully considered.  Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine.  Protamine sulfate should not be given when bleeding occurs without prior heparin use.
}}
 
'''Protamines''' are small, [[arginine]]-rich, [[cell nucleus|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.<ref name="Balhorn_2007">{{cite journal | vauthors = Balhorn R | title = The protamine family of sperm nuclear proteins | journal = Genome Biology | volume = 8 | issue = 9 | pages = 227 | year = 2007 | pmid = 17903313 | pmc = 2375014 | doi = 10.1186/gb-2007-8-9-227 }}</ref>
<!--Adult Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Adult)-->
 
|fdaLIADAdult=
 
=====Heparin Overdosage=====
 
* Dosing Information
 
:* Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.
 
:* Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses '''not to exceed 50 mg'''.
 
:* Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used.  Diluted solutions should not be stored since they contain no preservative.
 
:* Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.
 
:* Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin.  For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.
 
:* The dosage of protamine sulfate should be guided by blood coagulation studies.
 
:* Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.
 
<!--Off-Label Use and Dosage (Adult)-->
 
<!--Guideline-Supported Use (Adult)-->
 
|offLabelAdultGuideSupport=
 
=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Non–Guideline-Supported Use (Adult)-->
 
|offLabelAdultNoGuideSupport=
 
=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
 
<!--Pediatric Indications and Dosage-->
 
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
 
|fdaLIADPed=
 
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* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
 
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=====Condition1=====
 
* Developed by:
 
* Class of Recommendation:
 
* Strength of Evidence:
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
 
<!--Non–Guideline-Supported Use (Pediatric)-->
 
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=====Condition1=====
 
* Dosing Information
 
:* Dosage
 
=====Condition2=====
 
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<!--Contraindications-->
 
|contraindications=
 
* Condition1
 
<!--Warnings-->
 
|warnings=
 
* Description
 
====Precautions====
 
* Description
 
<!--Adverse Reactions-->
 
<!--Clinical Trials Experience-->
 
|clinicalTrials=
 
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
 
=====Cardiovascular=====
 
 
 
 
=====Digestive=====
 
 
 
 
=====Endocrine=====
 
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
 
=====Metabolic and Nutritional=====
 
 
 
 
=====Musculoskeletal=====
 
 
 
 
=====Neurologic=====
 
 
 
 
=====Respiratory=====
 
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
 
=====Special Senses=====
 
 
 
 
=====Urogenital=====
 
 
 
 
=====Miscellaneous=====
 
 
 
<!--Postmarketing Experience-->
 
|postmarketing=
 
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
 
=====Body as a Whole=====
 
 
 
=====Cardiovascular=====
 
 
 
=====Digestive=====
 
 
 
=====Endocrine=====
 
 
 
=====Hematologic and Lymphatic=====
 
 
 
=====Metabolic and Nutritional=====
 
 
 
=====Musculoskeletal=====
 
 
 
=====Neurologic=====
 
 
 
=====Respiratory=====
 
 
 
=====Skin and Hypersensitivy Reactions=====
 
 
 
=====Special Senses=====
 
 
 
=====Urogenital=====
 
 
 
=====Miscellaneous=====
 
 
 
<!--Drug Interactions-->
 
|drugInteractions=
 
* Drug
:* Description
 
<!--Use in Specific Populations-->
 
|useInPregnancyFDA=
* '''Pregnancy Category'''
 
|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
 
|useInLaborDelivery=
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
 
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
 
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
 
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
 
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
 
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
 
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
 
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
 
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
 
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
 
<!--Administration and Monitoring-->
 
|administration=
 
* Oral
 
* Intravenous
 
|monitoring=
 
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
 
=====Condition1=====
 
* Description
 
<!--IV Compatibility-->
 
|IVCompat=
 
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
 
<!--Overdosage-->
 
|overdose=
 
===Acute Overdose===
 
====Signs and Symptoms====
 
* Description
 
====Management====
 
* Description
 
===Chronic Overdose===
 
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacology-->
 
<!--Drug box 2-->
 
|drugBox=
 
 
 
<!--Mechanism of Action-->
 
|mechAction=
 
*
 
<!--Structure-->
 
|structure=
 
*
 
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
 
<!--Pharmacodynamics-->
 
|PD=
 
There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
 
<!--Pharmacokinetics-->
 
|PK=
 
There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
 
<!--Nonclinical Toxicology-->
 
|nonClinToxic=
 
There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
 
<!--Clinical Studies-->
 
|clinicalStudies=
 
There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
 
=====Condition1=====
 
* Description
 
<!--How Supplied-->
 
|howSupplied=
 
*
 
<!--Patient Counseling Information-->
 
|fdaPatientInfo=
 
There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
 
<!--Precautions with Alcohol-->
 
|alcohol=


* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
== 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.<ref>{{cite journal | vauthors = Brewer LR, Corzett M, Balhorn R | title = Protamine-induced condensation and decondensation of the same DNA molecule | journal = Science | volume = 286 | issue = 5437 | pages = 120–3 | date = Oct 1999 | pmid = 10506559 | doi = 10.1126/science.286.5437.120 }}</ref> 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.<ref>{{cite journal | vauthors = Woop M | title = Optimizing Tethered Particle Motion to Measure DNA Compaction by Protamine | journal = Biophysical Journal |volume=108 | page = 393a | date=January 2015 | doi=10.1016/j.bpj.2014.11.2156}}</ref>


<!--Brand Names-->
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.<ref>{{cite journal | vauthors = Lüke L, Campbell P, Varea Sánchez M, Nachman MW, Roldan ER | title = Sexual selection on protamine and transition nuclear protein expression in mouse species | journal = Proceedings of the Royal Society B: Biological Sciences | volume = 281 | issue = 1783 | pages = 20133359 | date = May 2014 | pmid = 24671975 | doi = 10.1098/rspb.2013.3359 | pmc=3996607}}</ref>


|brandNames=
== Medical uses ==
When mixed with [[insulin]], protamines slow down the onset and increase the duration of insulin action (see [[NPH insulin]]).<ref name="pmid21668337">{{cite journal | vauthors = Owens DR | title = Insulin preparations with prolonged effect | journal = Diabetes Technology & Therapeutics | volume = 13 Suppl 1 | issue =  | pages = S5-14 | date = Jun 2011 | pmid = 21668337 | doi = 10.1089/dia.2011.0068 }}</ref>


* Protamine sulfate®<ref>{{Cite web | title = PROTAMINE SULFATE injection, solution | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bc755638-8797-43ab-be0b-4ea3ded3f644 }}</ref>
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.<ref name="pmid10596998">{{cite journal | vauthors = Carr JA, Silverman N | title = The heparin-protamine interaction. A review | journal = The Journal of Cardiovascular Surgery | volume = 40 | issue = 5 | pages = 659–66 | date = Oct 1999 | pmid = 10596998 }}</ref>


<!--Look-Alike Drug Names-->
[[Protamine sulfate]] is an antidote for [[heparin]] overdose.<ref name="pmid2857186">{{cite journal | vauthors = Weiler JM, Freiman P, Sharath MD, Metzger WJ, Smith JM, Richerson HB, Ballas ZK, Halverson PC, Shulan DJ, Matsuo S | title = Serious adverse reactions to protamine sulfate: are alternatives needed? | journal = The Journal of Allergy and Clinical Immunology | volume = 75 | issue = 2 | pages = 297–303 | date = Feb 1985 | pmid = 2857186 | doi = 10.1016/0091-6749(85)90061-2 }}</ref>  A chain shortened version of protamine also acts as a potent heparin antagonist, but with markedly reduced [[antigenicity]].<ref name="pmid10926141">{{cite journal | vauthors = Byun Y, Chang LC, Lee LM, Han IS, Singh VK, Yang VC | title = Low molecular weight protamine: a potent but nontoxic antagonist to heparin/low molecular weight protamine | journal = ASAIO Journal | volume = 46 | issue = 4 | pages = 435–9 | year = 2000 | pmid = 10926141 | doi = 10.1097/00002480-200007000-00013 }}</ref>


|lookAlike=
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<ref name="Cornetta 1989">{{cite journal | vauthors = Cornetta K, Anderson WF | title = Protamine sulfate as an effective alternative to polybrene in retroviral-mediated gene-transfer: implications for human gene therapy | journal = Journal of Virological Methods | volume = 23 | issue = 2 | pages = 187–94 | date = Feb 1989 | pmid = 2786000 | doi = 10.1016/0166-0934(89)90132-8 | url = http://www.sciencedirect.com/science/article/pii/0166093489901328 }}</ref> and nonviral (e.g. utilizing cationic liposomes)<ref name="Sorgi 1997">{{cite journal | vauthors = Sorgi FL, Bhattacharya S, Huang L | title = Protamine sulfate enhances lipid-mediated gene transfer | journal = Gene Therapy | volume = 4 | issue = 9 | pages = 961–8 | date = Sep 1997 | pmid = 9349433 | doi = 10.1038/sj.gt.3300484 | url = http://www.nature.com/gt/journal/v4/n9/pdf/3300484a.pdf }}</ref> mediated delivery mechanisms.


* protamine — Protonix®<ref name="www.ismp.org">{{Cite web  | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref>
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.<ref>{{cite journal | vauthors = Duarte-Vázquez MA, García-Padilla S, Olvera-Ochoa L, González-Romero KE, Acosta-Iñiguez J, De la Cruz-Cordero R, Rosado JL | title = Effect of protamine in obesity induced by high-fat diets in rats | journal = International Journal of Obesity | volume = 33 | issue = 6 | pages = 687–92 | date = Jun 2009 | pmid = 19434066 | doi = 10.1038/ijo.2009.78 }}</ref>


<!--Drug Shortage Status-->
== Examples ==
Mice, humans<ref name="Balhorn_2007"/> and certain fish have two or more different protamines, whereas the sperm of bull and boar,<ref name="pmid2320417">{{cite journal | vauthors = Maier WM, Nussbaum G, Domenjoud L, Klemm U, Engel W | title = The lack of protamine 2 (P2) in boar and bull spermatozoa is due to mutations within the P2 gene | journal = Nucleic Acids Research | volume = 18 | issue = 5 | pages = 1249–54 | date = Mar 1990 | pmid = 2320417 | pmc = 330441 | doi = 10.1093/nar/18.5.1249 }}</ref> 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.<ref>{{cite journal | vauthors = Bunick D, Balhorn R, Stanker LH, Hecht NB | title = Expression of the rat protamine 2 gene is suppressed at the level of transcription and translation | journal = Experimental Cell Research | volume = 188 | issue = 1 | pages = 147–52 | date = May 1990 | pmid = 2328773 | doi=10.1016/0014-4827(90)90290-q}}</ref>


|drugShortage=
=== Human ===
}}
The 2 human protamines are denoted {{Gene|PRM1}} and {{Gene|PRM2}}.


<!--Pill Image-->
=== 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 (''[[Sturgeon|Acipenser stellatus]]'')
*scylliorhinine from [[Squaliformes|dogfish]] (''Scylliorhinus'')


{{PillImage
== Protamine structure ==
|fileName=No image.jpg|This image is provided by the National Library of Medicine.
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.<ref name="Balhorn_2007"/>
|drugName=
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.<ref name="Balhorn_2007"/>
|NDC=
|drugAuthor=
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<!--Label Display Image-->
The secondary and tertiary structure of protamine is not known with certainty, but several proposals have been published.<ref name="pmid15452126">{{cite journal | vauthors = Martins RP, Ostermeier GC, Krawetz SA | title = Nuclear matrix interactions at the human protamine domain: a working model of potentiation | journal = The Journal of Biological Chemistry | volume = 279 | issue = 50 | pages = 51862–8 | date = Dec 2004 | pmid = 15452126 | doi = 10.1074/jbc.M409415200 }}</ref><ref name="pmid14990583">{{cite journal | vauthors = Vilfan ID, Conwell CC, Hud NV | title = Formation of native-like mammalian sperm cell chromatin with folded bull protamine | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 20088–95 | date = May 2004 | pmid = 14990583 | doi = 10.1074/jbc.M312777200 }}</ref><ref name="pmid16442565">{{cite journal | vauthors = Biegeleisen K | title = The probable structure of the protamine-DNA complex | journal = Journal of Theoretical Biology | volume = 241 | issue = 3 | pages = 533–40 | date = Aug 2006 | pmid = 16442565 | doi = 10.1016/j.jtbi.2005.12.015 }}</ref>


{{LabelImage
== References ==
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
{{Reflist|33em}}
}}


{{LabelImage
== External links ==
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
* {{MeshName|Protamines}}
}}
* {{ATC|V03|AB14}}


<!--Category-->
{{Antidotes}}


[[Category:Cardiovascular Drugs]]
[[Category:Proteins]]
[[Category:Drug]]

Latest revision as of 09:08, 10 January 2019

Protamine P1
Identifiers
SymbolProtamine_P1
PfamPF00260
InterProIPR000221
PROSITEPDOC00047
protamine 1
Identifiers
SymbolPRM1
Entrez5619
HUGO9447
OMIM182880
RefSeqNM_002761
UniProtP04553
Other data
LocusChr. 16 p13.13
protamine 2
Identifiers
SymbolPRM2
Entrez5620
HUGO9448
OMIM182890
RefSeqNM_002762
UniProtP04554
Other data
LocusChr. 16 p13.13

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]

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:

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

  1. ↑ 1.0 1.1 1.2 1.3 Balhorn 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ Carr JA, Silverman N (Oct 1999). "The heparin-protamine interaction. A review". The Journal of Cardiovascular Surgery. 40 (5): 659–66. PMID 10596998.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Sorgi FL, Bhattacharya S, Huang L (Sep 1997). "Protamine sulfate enhances lipid-mediated gene transfer" (PDF). Gene Therapy. 4 (9): 961–8. doi:10.1038/sj.gt.3300484. PMID 9349433.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.

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