Periplasm

Last updated December 11, 2023

The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the periplasmic space in gram-negative (more accurately "diderm") 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.^[1]^[2] 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.^[3]

Terminology

Although bacteria are conventionally divided into two main groups—gram-positive and gram-negative, based upon their 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.^[4]^[5]^[6]^[7] 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.^[4]^[8]

Monoderm bacteria have a thin periplasm between the cell wall and the plasma membrane Gram-Cell-wall.svg — Monoderm bacteria have a thin periplasm between the cell wall and the plasma membrane

All gram-positive bacteria are bounded by a single unit lipid membrane (i.e. monoderm); they generally contain a thick layer (20-80 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 prokaryotes" has been proposed.^[4]^[8] 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 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.^[4]^[8] 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).^[4]^[5]^[8]^[9]

Structure

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.^[10]^[11] 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.^[12] 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.^[12]

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).^[13] Importantly, the periplasm is devoid of ATP. Several types of enzyme are present in the periplasm including alkaline phosphatases, cyclic phosphodiesterases, acid phosphatases and 5’-nucleotidases.^[14] 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 E. Coli.^[15] 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.^[16]

Figure demonstrating modulation of RcsF signaling by changes in the periplasmic intermembrane distance Rcsfsignalingmechanism.jpg — Figure demonstrating modulation of RcsF signaling by changes in the periplasmic intermembrane distance

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.^[17] Furthermore, the separation of the periplasm from the cytoplasm allows for the compartmentalization of enzymes that could be toxic in the cytoplasm.^[17] Some peptidoglycans and lipoproteins 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.^[17] 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.^[18]^[17]

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.^[19] Gram-negative bacteria tend to be more antimicrobial resistant than gram-positive bacteria, and also possess a much more significant periplasmic space between their two membrane bilayers. Since eukaryotes do not possess a periplasmic space, structures and enzymes found in the gram-negative periplasm are attractive targets for antimicrobial drug therapies.^[20] Additionally, vital functions such as facilitation of protein folding, protein transport, cell signaling, structural integrity, and nutrient uptake are performed by periplasm components,^[17] making it rich in potential drug targets. Aside from 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.^[21] 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.^[22]

The periplasmic space is deeply interconnected with the pathogenesis of disease in the setting of microbial infection. Many of the virulence factors associated with bacterial pathogenicity are secretion proteins, which are often subject to post-translational modification including disulfide bond formation.^[23] 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.^[23] 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,^[17]^[23] 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.^[24]^[25] Furthermore, the periplasm is also relevant to clinical developments by way of its role in mediating the uptake of transforming DNA.^[16]

Related Research Articles

<span class="mw-page-title-main">Gram stain</span> Investigative procedure in microbiology

Gram stain, is a method of staining used to classify bacterial species into two large groups: gram-positive bacteria and gram-negative bacteria. It may also be used to diagnose a fungal infection. The name comes from the Danish bacteriologist Hans Christian Gram, who developed the technique in 1884.

In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.

Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall sandwiched between an inner membrane (cytoplasmic), and an outer membrane.

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

Bdellovibrio is a genus of Gram-negative, obligate aerobic bacteria. One of the more notable characteristics of this genus is that members can prey upon other Gram-negative bacteria and feed on the biopolymers, e.g. proteins and nucleic acids, of their hosts. They have two lifestyles: a host-dependent, highly mobile phase, the "attack phase", in which they form "bdelloplasts" in their host bacteria; and a slow-growing, irregularly shaped, host-independent form.

The cell envelope comprises the inner cell membrane and the cell wall of a bacterium. In gram-negative bacteria an outer membrane is also included. This envelope is not present in the Mollicutes where the cell wall is absent.

The bacterium, despite its simplicity, contains a well-developed cell structure which is responsible for some of its unique biological structures and pathogenicity. Many structural features are unique to bacteria and are not found among archaea or eukaryotes. Because of the simplicity of bacteria relative to larger organisms and the ease with which they can be manipulated experimentally, the cell structure of bacteria has been well studied, revealing many biochemical principles that have been subsequently applied to other organisms.

Lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages in order to cleave the host's cell wall during the final stage of the lytic cycle. Lysins are highly evolved enzymes that are able to target one of the five bonds in peptidoglycan (murein), the main component of bacterial cell walls, which allows the release of progeny virions from the lysed cell. Cell-wall-containing Archaea are also lysed by specialized pseudomurein-cleaving lysins, while most archaeal viruses employ alternative mechanisms. Similarly, not all bacteriophages synthesize lysins: some small single-stranded DNA and RNA phages produce membrane proteins that activate the host's autolytic mechanisms such as autolysins.

DsbA is a bacterial thiol disulfide oxidoreductase (TDOR). DsbA is a key component of the Dsb family of enzymes. DsbA catalyzes intrachain disulfide bond formation as peptides emerge into the cell's periplasm.

There are several models of the Branching order of bacterial phyla, one of these was proposed in 2001 by Gupta based on conserved indels or protein, termed "protein signatures", an alternative approach to molecular phylogeny. Some problematic exceptions and conflicts are present to these conserved indels, however, they are in agreement with several groupings of classes and phyla. One feature of the cladogram obtained with this method is the clustering of cell wall morphology from monoderms to transitional diderms to traditional diderms.

Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory cell. It takes place in the form of Golgi membrane-bound micro-sized vesicles, termed membrane vesicles (MVs).

Outer membrane vesicles (OMVs) are vesicles released from the outer membranes of Gram-negative bacteria. While Gram-positive bacteria release vesicles as well those vesicles fall under the broader category of bacterial membrane vesicles (MVs). OMVs were the first MVs to be discovered, and are distinguished from outer inner membrane vesicles (OIMVS), which are gram-negative baterial vesicles containing portions of both the outer and inner bacterial membrane. Outer membrane vesicles were first discovered and characterized using transmission-electron microscopy by Indian Scientist Prof. Smriti Narayan Chatterjee and J. Das in 1966-67. OMVs are ascribed the functionality to provide a manner to communicate among themselves, with other microorganisms in their environment and with the host. These vesicles are involved in trafficking bacterial cell signaling biochemicals, which may include DNA, RNA, proteins, endotoxins and allied virulence molecules. This communication happens in microbial cultures in oceans, inside animals, plants and even inside the human body.

The type 2 secretion system is a type of protein secretion machinery found in various species of Gram-negative bacteria, including many human pathogens such as Pseudomonas aeruginosa and Vibrio cholerae. The type II secretion system is one of six protein secretory systems commonly found in Gram-negative bacteria, along with the type I, type III, and type IV secretion systems, as well as the chaperone/usher pathway, the autotransporter pathway/type V secretion system, and the type VI secretion system. Like these other systems, the type II secretion system enables the transport of cytoplasmic proteins across the lipid bilayers that make up the cell membranes of Gram-negative bacteria. Secretion of proteins and effector molecules out of the cell plays a critical role in signaling other cells and in the invasion and parasitism of host cells.

The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
And finally, one (Ank) that shuttles inorganic pyrophosphate (PP_i) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family

The Disulfide bond oxidoreductase D (DsbD) family is a member of the Lysine Exporter (LysE) Superfamily. A representative list of proteins belonging to the DsbD family can be found in the Transporter Classification Base.

OBPgp279 is an endolysin that hydrolyzes peptidoglycan, a major constituent in bacterial membrane. OBPgp279 is found in Pseudomonas fluorescens phage OBP, which belongs in the Myoviridae family of bacteriophages. Because of its role in hydrolyzing the peptidoglycan layer, OBPgp279 is a key enzyme in the lytic cycle of the OBP bacteriophage; it allows the bacteriophage to lyse its host internally to escape. Unlike other endolysins, OBPgp279 does not rely on holins to perforate the inner bacterial membrane in order to reach the peptidoglycan layer. Although OBPgp279 is not a well-studied enzyme, it has garnered interest as a potential antibacterial protein due to its activity against multidrug-resistant gram-negative bacteria.

Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND superfamily includes seven families: the heavy metal efflux (HME), the hydrophobe/amphiphile efflux-1, the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the eukaryotic sterol homeostasis family, and the hydrophobe/amphiphile efflux-3 family. These RND systems are involved in maintaining homeostasis of the cell, removal of toxic compounds, and export of virulence determinants. They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant bacterial infections were reported in the 1940s after the first mass production of antibiotics. Most of the RND superfamily transport systems are made of large polypeptide chains. RND proteins exist primarily in gram-negative bacteria but can also be found in gram-positive bacteria, archaea, and eukaryotes.

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

<span class="mw-page-title-main">Darobactin</span> Chemical compound

Darobactin is an experimental antibiotic compound that may be effective against Gram-negative bacteria. If it can be developed into a human-compatible form it would be the first to come from an animal microbiome.

Undecaprenyl phosphate (UP), also known lipid-P, bactoprenol and C55-P., is a molecule with the primary function of trafficking polysaccharides across the cell membrane, largely contributing to the overall structure of the cell wall in Gram-positive bacteria. In some situations, UP can also be utilized to carry other cell-wall polysaccharides, but UP is the designated lipid carrier for peptidoglycan. During the process of carrying the peptidoglycan across the cell membrane, N-acetylglucosamine and N-acetylmuramic acid are linked to UP on the cytoplasmic side of the membrane before being carried across. UP works in a cycle of phosphorylation and dephosphorylation as the lipid carrier gets used, recycled, and reacts with undecaprenyl phosphate. This type of synthesis is referred to as de novo synthesis where a complex molecule is created from simpler molecules as opposed to a complete recycle of the entire structure.

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