Editing Periplasm

{{Short description|The region between the inner and outer membrane, or cell wall}}
The '''periplasm''' is a concentrated gel-like [[matrix (biology)|matrix]] in the space between the inner [[cytoplasm]]ic membrane and the [[bacterial outer membrane]] called the ''periplasmic space'' in [[Gram-negative]] (more accurately "diderm") [[bacterium|bacteria]]. Using [[cryo-electron microscopy]] it has been found that a much smaller periplasmic space is also present in [[Gram-positive bacteria]] (more accurately "monoderm"), between cell wall and the plasma membrane.<ref name="Matias_2005">{{cite journal | vauthors = Matias VR, Beveridge TJ | title = Cryo-electron microscopy reveals native polymeric cell wall structure in Bacillus subtilis 168 and the existence of a periplasmic space | journal = Molecular Microbiology | volume = 56 | issue = 1 | pages = 240–251 | date = April 2005 | pmid = 15773993 | doi = 10.1111/j.1365-2958.2005.04535.x | s2cid = 11013569 | doi-access = free }}</ref><ref name="Zuber_2006">{{cite journal | vauthors = Zuber B, Haenni M, Ribeiro T, Minnig K, Lopes F, Moreillon P, Dubochet J | title = Granular layer in the periplasmic space of gram-positive bacteria and fine structures of Enterococcus gallinarum and Streptococcus gordonii septa revealed by cryo-electron microscopy of vitreous sections | journal = Journal of Bacteriology | volume = 188 | issue = 18 | pages = 6652–6660 | date = September 2006 | pmid = 16952957 | pmc = 1595480 | doi = 10.1128/JB.00391-06 }}</ref> The periplasm may constitute up to 40% of the total cell volume of gram-negative bacteria, but is a much smaller percentage in gram-positive bacteria.<ref name="isbn3-540-42608-6">{{cite book | vauthors = Holst O, Seltmann G |title=The Bacterial Cell Wall |date= January 2002 |publisher=Springer |location=Berlin |isbn=3-540-42608-6 }}</ref>

== Terminology ==
Although [[bacteria]] are conventionally divided into two main groups—Gram-positive and Gram-negative, based upon their [[Gram stain|Gram-stain]] retention property—this classification system is ambiguous as it can refer to three distinct aspects (staining result, cell-envelope organization, taxonomic group), which do not necessarily coalesce for some bacterial species.<ref name="Gupta_1998">{{cite journal | vauthors = Gupta RS | title = Protein phylogenies and signature sequences: A reappraisal of evolutionary relationships among archaebacteria, eubacteria, and eukaryotes | journal = Microbiology and Molecular Biology Reviews | volume = 62 | issue = 4 | pages = 1435–1491 | date = December 1998 | pmid = 9841678 | pmc = 98952 | doi = 10.1128/MMBR.62.4.1435-1491.1998 }}</ref><ref name="Gupta_2009">{{cite journal | vauthors = Gupta RS | title = The natural evolutionary relationships among prokaryotes | journal = Critical Reviews in Microbiology | volume = 26 | issue = 2 | pages = 111–131 | date = 2000 | pmid = 10890353 | doi = 10.1080/10408410091154219 | s2cid = 30541897 }}</ref><ref name="Desvaux_2009">{{cite journal | vauthors = Desvaux M, Hébraud M, Talon R, Henderson IR | title = Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue | journal = Trends in Microbiology | volume = 17 | issue = 4 | pages = 139–145 | date = April 2009 | pmid = 19299134 | doi = 10.1016/j.tim.2009.01.004 }}</ref><ref name="Sutcliffe_2010">{{cite journal | vauthors = Sutcliffe IC | title = A phylum level perspective on bacterial cell envelope architecture | journal = Trends in Microbiology | volume = 18 | issue = 10 | pages = 464–470 | date = October 2010 | pmid = 20637628 | doi = 10.1016/j.tim.2010.06.005 }}</ref> 
In most situations such as in this article, Gram-staining reflects the marked differences in the [[ultrastructure]] and chemical composition of the two main kinds of bacteria. The usual "Gram-positive" type does not have an outer lipid membrane, while the typical "Gram-negative" bacterium does.  The terms "diderm" and "monoderm", coined to refer to this distinction ''only'', is a more reliable and fundamental characteristic of the bacterial cells.<ref name="Gupta_1998" /><ref name="Gupta_1998b">{{cite journal | vauthors = Gupta RS | title = What are archaebacteria: life's third domain or monoderm prokaryotes related to gram-positive bacteria? A new proposal for the classification of prokaryotic organisms | journal = Molecular Microbiology | volume = 29 | issue = 3 | pages = 695–707 | date = August 1998 | pmid = 9723910 | doi = 10.1046/j.1365-2958.1998.00978.x | s2cid = 41206658 }}</ref>
[[File:Gram-Cell-wall.svg|thumb|Monoderm bacteria have a thin periplasm between the cell wall and the plasma membrane<ref name="Zuber_2006" />]]

All [[Gram-positive bacteria]] are bounded by a single unit lipid membrane (i.e. monoderm); they generally contain a thick layer (20-80&nbsp;nm) of peptidoglycan responsible for retaining the Gram-stain. A number of other bacteria which are bounded by a single membrane but stain gram-negative due to either lack of the peptidoglycan layer (viz., mycoplasmas) or their inability to retain the Gram-stain due to their cell wall composition, also show close relationship to the Gram-positive bacteria. For the bacterial (prokaryotic) cells that are bounded by a single cell membrane the term "monoderm bacteria" or "monoderm [[prokaryote]]s" has been proposed.<ref name="Gupta_1998" /><ref name="Gupta_1998b" /> In contrast to gram-positive bacteria, all archetypical Gram-negative bacteria are bounded by a cytoplasmic membrane as well as an outer cell membrane; they contain only a thin layer of peptidoglycan (2–3&nbsp;nm) between these membranes. The presence of both inner and outer cell membranes forms and define the periplasmic space or periplasmic compartment. These bacterial cells with two membranes have been designated as diderm bacteria.<ref name="Gupta_1998" /><ref name="Gupta_1998b" /> The distinction between the monoderm and diderm prokaryotes is supported by [[conserved signature indels]] in a number of important proteins (for example, [[DnaK]] and [[GroEL]]).<ref name="Gupta_1998" /><ref name="Gupta_2009" /><ref name="Gupta_1998b" /><ref name="Gupta_2011">{{cite journal | vauthors = Gupta RS | title = Origin of diderm (Gram-negative) bacteria: antibiotic selection pressure rather than endosymbiosis likely led to the evolution of bacterial cells with two membranes | journal = Antonie van Leeuwenhoek | volume = 100 | issue = 2 | pages = 171–182 | date = August 2011 | pmid = 21717204 | pmc = 3133647 | doi = 10.1007/s10482-011-9616-8 }}</ref>

== Structure ==
[[Image:Gram negative cell wall.svg|thumb|right|400px|[[Gram-negative]] (diderm) [[cell wall]]]]As shown in the figure to the right, the periplasmic space in gram-negative or diderm bacteria is located between the inner and outer membrane of the cell. The periplasm contains peptidoglycan and the membranes that enclose the periplasmic space contain many integral membrane proteins, which can participate in [[cell signaling]]. Furthermore, the periplasm houses motility organelles such as the [[flagellum]], which spans both membranes enclosing the periplasm. The periplasm is described as gel-like due to the high abundance of proteins and peptidoglycan. The periplasm occupies 7% to 40% of the total volume of diderm bacteria, and contains up to 30% of cellular proteins.<ref>{{Cite journal |last=Prochnow |first=Hans |last2=Fetz |first2=Verena |last3=Hotop |first3=Sven-Kevin |last4=García-Rivera |first4=Mariel A. |last5=Heumann |first5=Axel |last6=Brönstrup |first6=Mark |date=2019-02-05 |title=Subcellular Quantification of Uptake in Gram-Negative Bacteria |url=https://pubs.acs.org/doi/10.1021/acs.analchem.8b03586 |journal=Analytical Chemistry |language=en |volume=91 |issue=3 |pages=1863–1872 |doi=10.1021/acs.analchem.8b03586 |issn=0003-2700|hdl=10033/621709 |hdl-access=free }}</ref><ref>{{Cite journal |last=Weiner |first=Joel H. |last2=Li |first2=Liang |date=September 2008 |title=Proteome of the Escherichia coli envelope and technological challenges in membrane proteome analysis |url=https://linkinghub.elsevier.com/retrieve/pii/S0005273607002787 |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |language=en |volume=1778 |issue=9 |pages=1698–1713 |doi=10.1016/j.bbamem.2007.07.020|url-access=subscription }}</ref> The structure of the monoderm periplasm differs from that of diderm bacteria as the so-called periplasmic space in monoderm bacteria is not enclosed by two membranes but is rather enclosed by the cytoplasmic membrane and the peptidoglycan layer beneath.<ref name="Forster-2012">{{Cite journal |last=Forster |first=Brian M. |last2=Marquis |first2=Hélène |date=May 2012 |title=Protein transport across the cell wall of monoderm Gram‐positive bacteria |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2958.2012.08040.x |journal=Molecular Microbiology |language=en |volume=84 |issue=3 |pages=405–413 |doi=10.1111/j.1365-2958.2012.08040.x |issn=0950-382X |pmc=3331896 |pmid=22471582}}</ref> For this reason, the monoderm periplasmic space is also referred to as the inner-wall zone (IWZ). The IWZ serves as the first destination of translocation for proteins being transported across the monoderm bacterial cell wall.<ref name="Forster-2012" />

== Function ==
In [[diderm bacteria]], the periplasm contains a thin [[cell wall]] composed of [[peptidoglycan]]. In addition, it includes solutes such as ions and proteins, which are involved in wide variety of functions ranging from nutrient binding, transport, folding, degradation, substrate hydrolysis, to peptidoglycan synthesis, [[electron transport]], and alteration of substances toxic to the cell ([[xenobiotic metabolism]]).<ref name="isbn0-07-295175-3">{{cite book | vauthors = Klein DW, Prescott LM, Harley J |title=Microbiology |publisher=McGraw-Hill Higher Education |location=Boston |year=2005 |isbn=0-07-295175-3 }}</ref> Importantly, the periplasm is devoid of [[adenosine triphosphate|ATP]]. Several types of enzyme are present in the periplasm including [[alkaline phosphatase]]s, [[Cyclic nucleotide phosphodiesterase|cyclic phosphodiesterase]]s, [[acid phosphatase]]s and [[5'-nucleotidase|5’-nucleotidase]]s.<ref>{{cite journal | vauthors = Neu HC, Heppel LA | title = The release of enzymes from Escherichia coli by osmotic shock and during the formation of spheroplasts | journal = The Journal of Biological Chemistry | volume = 240 | issue = 9 | pages = 3685–3692 | date = September 1965 | pmid = 4284300 | doi = 10.1016/S0021-9258(18)97200-5 | doi-access = free }}</ref> Of note, the periplasm also contains enzymes important for the facilitation of [[protein folding]]. For example, disulfide bond protein A (DsbA) and disulfide bond protein C (DsbC), which are responsible for catalyzing peptide bond formation and isomerization, respectively, were identified in the periplasm of ''[[Escherichia coli|E. Coli]].''<ref>{{cite journal | vauthors = Denoncin K, Collet JF | title = Disulfide bond formation in the bacterial periplasm: major achievements and challenges ahead | journal = Antioxidants & Redox Signaling | volume = 19 | issue = 1 | pages = 63–71 | date = July 2013 | pmid = 22901060 | pmc = 3676657 | doi = 10.1089/ars.2012.4864 }}</ref> As disulfide bond formation is frequently a rate-limiting step in the folding of proteins, these oxidizing enzymes play an important role in the bacteria periplasm. In addition, the periplasm mediates the uptake of DNA in several strains of transformable bacteria.<ref name="Hahn_2021">{{cite journal | vauthors = Hahn J, DeSantis M, Dubnau D | title = Mechanisms of Transforming DNA Uptake to the Periplasm of Bacillus subtilis | journal = mBio | volume = 12 | issue = 3 | pages = e0106121 | date = June 2021 | pmid = 34126763 | pmc = 8262900 | doi = 10.1128/mBio.01061-21 | veditors = Freitag NE }}</ref> 
[[File:Rcsfsignalingmechanism.jpg|thumb|Figure demonstrating modulation of RcsF signaling by changes in the periplasmic intermembrane distance<ref name="Miller_2018"/>]]
The compartmentalization afforded by the periplasmic space gives rise to several important functions. Aside from those previously mentioned, the periplasm also functions in protein transport and quality control, analogous to the [[endoplasmic reticulum]] in eukaryotes.<ref name="Miller_2018">{{cite journal | vauthors = Miller SI, Salama NR | title = The gram-negative bacterial periplasm: Size matters | journal = PLOS Biology | volume = 16 | issue = 1 | pages = e2004935 | date = January 2018 | pmid = 29342145 | pmc = 5771553 | doi = 10.1371/journal.pbio.2004935 | doi-access = free }}</ref> Furthermore, the separation of the periplasm from the cytoplasm allows for the compartmentalization of enzymes that could be toxic in the cytoplasm.<ref name="Miller_2018" /> Some [[peptidoglycan]]s and [[lipoprotein]]s located in the periplasm provide a structural support system for the cell that aids in promoting the cell's ability to withstand turgor pressure. Notably, organelles such as the [[flagellum]] require the assembly of polymers within the periplasm for proper functioning. As the driveshaft of the flagellum spans the periplasmic space, its length is dictated by positioning of the outer membrane as induced by its contraction, which is mediated by periplasmic polymers.<ref name="Miller_2018" /> The periplasm also functions in [[cell signaling]], such as in the case of the lipoprotein RcsF, which has a globular domain residing in the periplasm and acts as a stress sensor. When RcsF fails to interact with BamA, such as in the case of an enlarged periplasm, RcsF is not exported to the cell surface and are able to trigger the Rcs signaling cascade. Periplasm size, therefore, plays an important role in stress signaling.<ref>{{cite journal | vauthors = Rodríguez-Alonso R, Létoquart J, Nguyen VS, Louis G, Calabrese AN, Iorga BI, Radford SE, Cho SH, Remaut H, Collet JF | display-authors = 6 | title = Structural insight into the formation of lipoprotein-β-barrel complexes | journal = Nature Chemical Biology | volume = 16 | issue = 9 | pages = 1019–1025 | date = September 2020 | pmid = 32572278 | pmc = 7610366 | doi = 10.1038/s41589-020-0575-0 }}</ref><ref name="Miller_2018" />

== Clinical significance ==
As bacteria are the responsible pathogen for many infections and illnesses, the biochemical and structural components that distinguish disease causing bacterial cells from native eukaryotic cells are of great interest from a clinical perspective.<ref>{{cite journal | vauthors = Prestinaci F, Pezzotti P, Pantosti A | title = Antimicrobial resistance: a global multifaceted phenomenon | journal = Pathogens and Global Health | volume = 109 | issue = 7 | pages = 309–318 | date = 2015-10-03 | pmid = 26343252 | pmc = 4768623 | doi = 10.1179/2047773215Y.0000000030 }}</ref> Gram-negative bacteria tend to be more [[Antimicrobial resistance|antimicrobial resistant]] than gram-positive bacteria, and also possess a much more significant periplasmic space between their two membrane bilayers. Since [[Eukaryote|eukaryotes]] do not possess a periplasmic space, structures and enzymes found in the gram-negative periplasm are attractive targets for antimicrobial drug therapies.<ref>{{cite journal | vauthors = Pandeya A, Ojo I, Alegun O, Wei Y | title = Periplasmic Targets for the Development of Effective Antimicrobials against Gram-Negative Bacteria | journal = ACS Infectious Diseases | volume = 6 | issue = 9 | pages = 2337–2354 | date = September 2020 | pmid = 32786281 | pmc = 8187054 | doi = 10.1021/acsinfecdis.0c00384 }}</ref> Additionally, vital functions such as facilitation of protein folding, protein transport, cell signaling, structural integrity, and nutrient uptake are performed by periplasm components,<ref name="Miller_2018" /> making it rich in potential drug targets. Aside from [[Enzyme|enzymes]] and structural components that are vital to cell function and survival, the periplasm also contains virulence-associated proteins such as DsbA that can be targeted by antimicrobial therapies.<ref>{{cite journal | vauthors = Ha UH, Wang Y, Jin S | title = DsbA of Pseudomonas aeruginosa is essential for multiple virulence factors | journal = Infection and Immunity | volume = 71 | issue = 3 | pages = 1590–1595 | date = March 2003 | pmid = 12595484 | pmc = 148828 | doi = 10.1128/IAI.71.3.1590-1595.2003 }}</ref> Due to their role in catalyzing disulfide bond formation for a variety of virulence factors, the DsbA/DsbB system has been of particular interest as a target for anti-virulence drugs.<ref>{{cite journal | vauthors = Smith RP, Paxman JJ, Scanlon MJ, Heras B | title = Targeting Bacterial Dsb Proteins for the Development of Anti-Virulence Agents | journal = Molecules | volume = 21 | issue = 7 | pages = 811 | date = July 2016 | pmid = 27438817 | pmc = 6273893 | doi = 10.3390/molecules21070811 | doi-access = free }}</ref>

The periplasmic space is deeply interconnected with the pathogenesis of disease in the setting of microbial infection. Many of the [[Virulence factor|virulence factors]] associated with bacterial pathogenicity are secretion proteins, which are often subject to post-translational modification including disulfide bond formation.<ref name="Łasica_2007">{{cite journal | vauthors = Łasica AM, Jagusztyn-Krynicka EK | title = The role of Dsb proteins of Gram-negative bacteria in the process of pathogenesis | journal = FEMS Microbiology Reviews | volume = 31 | issue = 5 | pages = 626–636 | date = September 2007 | pmid = 17696887 | doi = 10.1111/j.1574-6976.2007.00081.x | doi-access = free }}</ref> The oxidative environment of the periplasm contains Dsb (disulfide bond formation) proteins that catalyze such post-translational modifications, and therefore play an important role in establishing virulence factor tertiary and quaternary structure essential for proper protein function.<ref name="Łasica_2007" /> In addition to Dsb proteins found in the periplasm, motility organelles such as the flagellum are also essential for host infection. The flagellum is rooted in the periplasm and is stabilized by interaction with periplasmic structural components,<ref name="Miller_2018" /><ref name="Łasica_2007" /> and is therefore another pathogenesis-related target for antimicrobial agents. During infection of a host, the cell of a bacterium is subject to many turbulent environmental conditions, which highlights the importance of the structural integrity afforded by the periplasm. In particular, peptidoglycan synthesis is vital to cell wall production, and inhibitors of peptidoglycan synthesis have been of clinical interest for targeting bacteria for many decades.<ref>{{cite journal | vauthors = Puls JS, Brajtenbach D, Schneider T, Kubitscheck U, Grein F | title = Inhibition of peptidoglycan synthesis is sufficient for total arrest of staphylococcal cell division | journal = Science Advances | volume = 9 | issue = 12 | pages = eade9023 | date = March 2023 | pmid = 36947615 | pmc = 10032595 | doi = 10.1126/sciadv.ade9023 | bibcode = 2023SciA....9E9023P }}</ref><ref>{{cite journal | vauthors = Linnett PE, Strominger JL | title = Additional antibiotic inhibitors of peptidoglycan synthesis | journal = Antimicrobial Agents and Chemotherapy | volume = 4 | issue = 3 | pages = 231–236 | date = September 1973 | pmid = 4202341 | pmc = 444534 | doi = 10.1128/AAC.4.3.231 }}</ref> Furthermore, the periplasm is also relevant to clinical developments by way of its role in mediating the uptake of [[Transformation (genetics)|transforming DNA]].<ref name="Hahn_2021" />

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = White D | title = The Physiology and Biochemistry of Prokaryotes | edition = 2nd | publisher = Oxford University Press | location = Oxford | date = 2000 | page = 22 | isbn = 978-0-19-512579-5 }}
{{refend}}

{{Bacteria}}

[[Category:Bacteriology]]
[[Category:Prokaryotic cell anatomy]]