Co- and Post-Translational Myristoylation

Myristoylation is a lipidation modification where a

myristoyl group Myristic acid (IUPAC name: tetradecanoic acid) is a common saturated fatty acid with the molecular formula CH3(CH2)12COOH. Its salts and esters are commonly referred to as myristates or tetradecanoates. It is named after the binomial name for nutm ...

, derived from

myristic acid Myristic acid (IUPAC name: tetradecanoic acid) is a common saturated fatty acid with the molecular formula CH3(CH2)12COOH. Its salts and esters are commonly referred to as myristates or tetradecanoates. It is named after the binomial name for nutm ...

, is

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

ly attached by an

amide bond In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is p ...

to the alpha-amino group of an

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

residue. Myristic acid is a 14-carbon saturated fatty acid (14:0) with the systematic name of ''n''-Tetradecanoic acid. This modification can be added either co-translationally or post-translationally. N-myristoyltransferase (NMT) catalyzes the

addition reaction in the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

of cells. This lipidation event is the most found type of fatty acylation and is common among many organisms including

animal Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

protozoan Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

s and

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

es. Myristoylation allows for weak protein–protein and protein–lipid interactions and plays an essential role in membrane targeting,

protein–protein interaction Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and th ...

s and functions widely in a variety of

signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

pathways.

Discovery

In 1982, Koiti Titani's lab identified an "N-terminal blocking group" on the catalytic subunit of cyclic AMP-dependent protein kinase in cows as ''n''-tetradecanoyl. Almost simultaneously in Claude B. Klee's lab, this same N-terminal blocking group was further characterized as myristic acid. Both labs made this discovery utilizing similar techniques:

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...

and

gas chromatography Gas chromatography (GC) is a common type of chromatography used in analytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. Typical uses of GC include testing the purity of a particular substance, ...

N-myristoyltransferase

The enzyme N-myristoyltransferase (NMT) or

glycylpeptide N-tetradecanoyltransferase In enzymology, a glycylpeptide N-tetradecanoyltransferase () is an enzyme that catalyzes the chemical reaction :tetradecanoyl-CoA + glycylpeptide \rightleftharpoons CoA + N-tetradecanoylglycylpeptide Thus, the two substrates of this enzyme ...

is responsible for the irreversible addition of a myristoyl group to N-terminal or internal glycine residues of proteins. This modification can occur co-translationally or

post-translational Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosomes ...

ly. In vertebrates, this modification is carried about by two NMTs, NMT1 and

NMT2 Glycylpeptide N-tetradecanoyltransferase 2 known also as N-myristoyltransferase, is an enzyme (EC: 2.3.1.97) that in humans is encoded by the ''NMT2'' gene. Function N-myristoyltransferase (NMT) catalyzes the reaction of N-terminal myristoy ...

, both of which are members of the GCN5

acetyltransferase Acetyltransferase (or transacetylase) is a type of transferase enzyme that transfers an acetyl group. Examples include: * Histone acetyltransferases including CBP histone acetyltransferase * Choline acetyltransferase * Chloramphenicol acetyltransf ...

superfamily.

Structure

The

crystal structure In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystal, crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric pat ...

of NMT reveals two identical subunits, each with its own myristoyl CoA binding site. Each subunit consists of a large saddle-shaped

β-sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

surrounded by

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

. The symmetry of the fold is pseudo twofold. Myristoyl CoA binds at the

portion, while the

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

end binds the protein.

Mechanism

The addition of the myristoyl group proceeds via a nucleophilic addition-elimination reaction. First, myristoyl coenzyme A (CoA) is positioned in its binding pocket of NMT so that the

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

faces two amino acid residues,

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

170 and

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...

171. This polarizes the carbonyl so that there is a net positive charge on the carbon, making it susceptible to nucleophilic attack by the

residue of the protein to be modified. When myristoyl CoA binds, NMT reorients to allow binding of the peptide. The C-terminus of NMT then acts as a general base to

deprotonate Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.edu ...

the NH₃⁺, activating the

amino group In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such a ...

to attack at the

carbonyl group In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

of myristoyl-CoA. The resulting

tetrahedral intermediate A tetrahedral intermediate is a reaction intermediate in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral. Tetrahedral intermediates result from nucleophilic addition to a c ...

is stabilized by the interaction between a positively charged

oxyanion hole An oxyanion hole is a pocket in the active site of an enzyme that stabilizes transition state negative charge on a deprotonated oxygen or alkoxide. The pocket typically consists of backbone amides or positively charged residues. Stabilising the t ...

and the negatively charged

alkoxide In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organic substituent. Alkoxides are strong bases and, whe ...

anion. Free CoA is then released, causing a

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...

in the enzyme that allows the release of the myristoylated peptide. Myristoylation mechanism

Co-translational vs. post-translational addition

Co-translational and post-translational covalent modifications enable proteins to develop higher levels of complexity in cellular function, further adding diversity to the

proteome The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or organism at a certain time. It is the set of expressed proteins in a given type of cell or organism, at a given time, under defined conditions. ...

. The addition of myristoyl-CoA to a protein can occur during protein translation or after. During co-translational addition of the myristoyl group, the N-terminal

is modified following cleavage of the N-terminal

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...

residue in the newly forming, growing

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

. Post-translational myristoylation typically occurs following a

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...

cleavage event, resulting in the exposure of an internal glycine residue, which is then available for myristic acid addition.

Functions

Myristoylated proteins

Myristoylation molecular switch

Myristoylation not only diversifies the function of a protein, but also adds layers of regulation to it. One of the most common functions of the myristoyl group is in membrane association and cellular localization of the modified protein. Though the myristoyl group is added onto the end of the protein, in some cases it is sequestered within

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

regions of the protein rather than solvent exposed. By regulating the orientation of the myristoyl group, these processes can be highly coordinated and closely controlled. Myristoylation is thus a form of "

molecular switch A molecular switch is a molecule that can be reversibly shifted between two or more stable states. The molecules may be shifted between the states in response to environmental stimuli, such as changes in pH, light, temperature, an electric curren ...

." Both hydrophobic myristoyl groups and "basic patches" (highly positive regions on the protein) characterize myristoyl-electrostatic switches. The basic patch allows for favorable

electrostatic interaction Electrostatics is a branch of physics that studies electric charges at rest (static electricity). Since classical times, it has been known that some materials, such as amber, attract lightweight particles after triboelectric effect, rubbing. ...

s to occur between the negatively charged phospholipid heads of the membrane and the positive surface of the associating protein. This allows tighter association and directed localization of proteins. Myristoyl-conformational switches can come in several forms.

Ligand binding In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...

to a myristoylated protein with its myristoyl group sequestered can cause a

in the protein, resulting in exposure of the myristoyl group. Similarly, some myristoylated proteins are activated not by a designated ligand, but by the exchange of

GDP Gross domestic product (GDP) is a monetary measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjective nature this measure is often ...

for GTP by

guanine nucleotide exchange factor Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structu ...

s in the cell. Once GTP is bound to the myristoylated protein, it becomes activated, exposing the myristoyl group. These conformational switches can be utilized as a signal for cellular localization, membrane-protein, and

Dual modifications of myristoylated proteins

Further modifications on N-myristoylated proteins can add another level of regulation for myristoylated protein. Dual

acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with ...

can facilitate more tightly regulated protein localization, specifically targeting proteins to

lipid rafts The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...

at membranes or allowing dissociation of myristoylated proteins from membranes. Myristoylation and

palmitoylation Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically lipid bilayer, memb ...

are commonly coupled modifications. Myristoylation alone can promote transient membrane interactions that enable proteins to anchor to membranes but dissociate easily. Further palmitoylation allows for tighter anchoring and slower dissociation from membranes when required by the cell. This specific dual modification is important for

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

pathways and is referred to as the dual fatty acylation switch. Myristoylation is often followed by

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of nearby residues. Additional phosphorylation of the same protein can decrease the electrostatic affinity of the myristoylated protein for the membrane, causing translocation of that protein to the cytoplasm following dissociation from the membrane.

Signal transduction

Myristoylation plays a vital role in membrane targeting and

in plant responses to environmental stress. In addition, in signal transduction via G protein,

of the α subunit,

prenylation Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...

of the γ subunit, and myristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor.

Apoptosis

Myristoylation is an integral part of

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, or programmed cell death. Apoptosis is necessary for cell homeostasis and occurs when cells are under stress such as

hypoxia Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of the specific environment * Hypoxia (medical), abnormally low level of oxygen in the tis ...

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

. Apoptosis can proceed by either mitochondrial or receptor mediated activation. In receptor mediated apoptosis, apoptotic pathways are triggered when the cell binds a death receptor. In one such case, death receptor binding initiates the formation of the

death-inducing signaling complex The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of its ...

, a complex composed of numerous proteins including several caspases, including

caspase 3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also p ...

. Caspase 3 cleaves a number of proteins that are subsequently myristoylated by NMT. The pro-apoptotic BH3-interacting domain death agonist (Bid) is one such protein that once myristoylated, translocates to the

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

where it prompts the release of

cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...

leading to cell death.

Actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

gelsolin Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency. Cellu ...

and p21-activated kinase 2

PAK2 Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the ''PAK2'' gene. PAK2 is one of three members of Group I PAK family of serine/threonine kinases. The PAKs are evolutionary conserved. PAK2 and its cleaved fragment ...

are three other proteins that are myristoylated following cleavage by

, which leads to either the up-regulation or down-regulation of apoptosis.

Impact on human health

Cancer

''c-Src'' is a gene that codes for proto-oncogene tyrosine-protein kinase Src, a protein important for normal mitotic cycling. It is phosphorylated and dephosphorylated to turn signaling on and off. Proto-oncogene tyrosine-protein kinase Src must be localized to the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

in order to phosphorylate other downstream targets; myristoylation is responsible for this membrane targeting event. Increased myristoylation of ''c-Src'' can lead to enhanced

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

and be responsible for transforming normal cells into cancer cells. Activation of ''c-Src'' can lead to the so-called

hallmarks of cancer The hallmarks of cancer were originally six biological capabilities acquired during the multistep development of human tumors and have since been increased to eight capabilities and two enabling capabilities. The idea was coined by Douglas Hanah ...

: upregulation of

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...

, proliferation, and

invasion An invasion is a military offensive in which large numbers of combatants of one geopolitical entity aggressively enter territory owned by another such entity, generally with the objective of either: conquering; liberating or re-establishing con ...

Viral infectivity

HIV-1 The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey, ...

is a

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

that relies on myristoylation of one of its structural proteins in order to successfully package its genome, assemble and mature into a new infectious particle.

Viral matrix protein Viral matrix proteins are structural proteins linking the viral envelope with the virus core. They play a crucial role in virus assembly, and interact with the RNP complex as well as with the viral membrane. They are found in many enveloped virus ...

, the N-terminal most domain of the gag polyprotein is myristoylated. This myristoylation modification targets gag to the membrane of the host cell. Utilizing the myristoyl-electrostatic switch, including a basic patch on the matrix protein,

gag A gag is usually an item or device designed to prevent speech, often as a restraint device to stop the subject from calling for help and keep its wearer silent. This is usually done by blocking the mouth, partially or completely, or attemptin ...

can assemble at

lipid raft The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...

s at the

for viral assembly, budding and further maturation. In order to prevent viral infectivity, myristoylation of the matrix protein could become a good drug target.

Prokaryotic and eukaryotic infections

Certain NMTs are therapeutic targets for development of drugs against bacterial

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

s. Myristoylation has been shown to be necessary for the survival of a number of disease-causing

, among them '' C. albicans'' and ''

C. neoformans ''Cryptococcus neoformans'' is an encapsulated yeast belonging to the class (biology), class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to ''Filobasid ...

''. In addition to

prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...

bacteria, the NMTs of numerous disease-causing

eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

organisms have been identified as

drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand (biochemistry), ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes ...

s as well. Proper NMT functioning in the

protozoa Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

Leishmania major ''Leishmania major'' is a species of parasite found in the genus '' Leishmania'', and is associated with the disease zoonotic cutaneous leishmaniasis (also known as Aleppo boil, Baghdad boil, Bay sore, Biskra button, Chiclero ulcer, Delhi boil, K ...

'' and ''

Leishmania donovani ''Leishmania donovani'' is a species of intracellular parasites belonging to the genus ''Leishmania'', a group of haemoflagellate kinetoplastids that cause the disease leishmaniasis. It is a human blood parasite responsible for visceral leishmani ...

'' (

leishmaniasis Leishmaniasis is a wide array of clinical manifestations caused by parasites of the trypanosome genus ''Leishmania''. It is generally spread through the bite of phlebotomine sandflies, ''Phlebotomus'' and ''Lutzomyia'', and occurs most freq ...

), ''

Trypanosoma brucei ''Trypanosoma brucei'' is a species of parasitic Kinetoplastida, kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclus ...

'' (

African sleeping sickness African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species '' Trypanosoma brucei''. Humans are infected by two ty ...

), and '' P. falciparum'' (

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

) is necessary for survival of the parasites. Inhibitors of these organisms are under current investigation. A

pyrazole Pyrazole is an organic compound with the formula C3H3N2H. It is a heterocycle characterized by a 5-membered ring of three carbon Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent ...

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

has been identified that selectively binds ''T. brucei'', competing for the peptide binding site, thus inhibiting enzymatic activity and eliminating the parasite from the bloodstream of mice with

References

External links

The MYR PredictorExPASy Myristoylation Tool
{{Protein posttranslational modification Post-translational modification Signal transduction