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84-858: See text Flavivirus , renamed Orthoflavivirus in 2023, is a genus of positive-strand RNA viruses in the family Flaviviridae . The genus includes the West Nile virus , dengue virus , tick-borne encephalitis virus , yellow fever virus , Zika virus and several other viruses which may cause encephalitis , as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including

168-692: A dead end host . The exceptions to this are the yellow fever virus , dengue virus and zika virus . These three viruses still require mosquito vectors but are well-enough adapted to humans as to not necessarily depend upon animal hosts (although they continue to have important animal transmission routes, as well). Other virus transmission routes for arboviruses include handling infected animal carcasses, blood transfusion, sex, childbirth and consumption of unpasteurised milk products. Transmission from nonhuman vertebrates to humans without an intermediate vector arthropod however mostly occurs with low probability. For example, early tests with yellow fever showed that

252-412: A slippery sequence in the mRNA that codes for the polypeptide causes ribosomal frameshifting , leading to two different lengths of peptidic chains ( a and ab ) at an approximately fixed ratio. Many proteins and hormones are synthesized in the form of their precursors - zymogens , proenzymes , and prehormones . These proteins are cleaved to form their final active structures. Insulin , for example,

336-521: A ubiquitin -dependent process that targets unwanted proteins to proteasome . The autophagy -lysosomal pathway is normally a non-selective process, but it may become selective upon starvation whereby proteins with peptide sequence KFERQ or similar are selectively broken down. The lysosome contains a large number of proteases such as cathepsins . The ubiquitin-mediated process is selective. Proteins marked for degradation are covalently linked to ubiquitin. Many molecules of ubiquitin may be linked in tandem to

420-597: A Binjari vaccine bearing the Zika virus structural proteins protected mice from disease after challenge . A similar approach employs the insect-specific alphavirus Eilat virus as a vaccine platform . ... These new vaccine platforms generated from insect-specific flaviviruses and alphaviruses represent affordable, efficient, and safe approaches to rapid development of infectious, attenuated vaccines against pathogens from these two virus families. Positive-strand RNA virus Positive-strand RNA viruses ( +ssRNA viruses ) are

504-411: A cascade of sequential proteolytic activation of many specific proteases, resulting in blood coagulation. The complement system of the immune response also involves a complex sequential proteolytic activation and interaction that result in an attack on invading pathogens. Protein degradation may take place intracellularly or extracellularly. In digestion of food, digestive enzymes may be released into

588-505: A distinct virus around 1000 years ago. This initial virus developed into two distinct lineages, lineage 1 and its multiple profiles is the source of the epidemic transmission in Africa and throughout the world. Lineage 2 was considered an Africa zoonosis . However, in 2008, lineage 2, previously only seen in horses in sub-Saharan Africa and Madagascar, began to appear in horses in Europe, where

672-426: A group of related viruses that have positive-sense , single-stranded genomes made of ribonucleic acid . The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated into viral proteins by the host cell's ribosomes . Positive-strand RNA viruses encode an RNA-dependent RNA polymerase (RdRp) which is used during replication of the genome to synthesize a negative-sense antigenome that

756-542: A number of highly conserved secondary structures which are conserved and restricted to the flavivirus family. The majority of analysis has been carried out using West Nile virus (WNV) to study the function the 3'UTR. Currently 8 secondary structures have been identified within the 3'UTR of WNV and are (in the order in which they are found with the 3'UTR) SL-I, SL-II, SL-III, SL-IV, DB1, DB2 and CRE. Some of these secondary structures have been characterised and are important in facilitating viral replication and protecting

840-479: A polypeptide during or after translation in protein synthesis often occurs for many proteins. This may involve removal of the N-terminal methionine , signal peptide , and/or the conversion of an inactive or non-functional protein to an active one. The precursor to the final functional form of protein is termed proprotein , and these proproteins may be first synthesized as preproprotein. For example, albumin

924-503: A positively charged residue ( arginine and lysine ); chymotrypsin cleaves the bond after an aromatic residue ( phenylalanine , tyrosine , and tryptophan ); elastase cleaves the bond after a small non-polar residue such as alanine or glycine. In order to prevent inappropriate or premature activation of the digestive enzymes (they may, for example, trigger pancreatic self-digestion causing pancreatitis ), these enzymes are secreted as inactive zymogen. The precursor of pepsin , pepsinogen ,

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1008-506: A protein destined for degradation. The polyubiquinated protein is targeted to an ATP-dependent protease complex, the proteasome. The ubiquitin is released and reused, while the targeted protein is degraded. Different proteins are degraded at different rates. Abnormal proteins are quickly degraded, whereas the rate of degradation of normal proteins may vary widely depending on their functions. Enzymes at important metabolic control points may be degraded much faster than those enzymes whose activity

1092-416: A protein, and proteins with segments rich in proline , glutamic acid , serine , and threonine (the so-called PEST proteins ) have short half-life. Other factors suspected to affect degradation rate include the rate deamination of glutamine and asparagine and oxidation of cystein , histidine , and methionine, the absence of stabilizing ligands, the presence of attached carbohydrate or phosphate groups,

1176-677: A result of the very high affinity for ribosomes by the viral genome's internal ribosome entry site (IRES) elements; in some viruses, such as poliovirus and rhinoviruses , normal protein synthesis is further disrupted by viral proteases degrading components required to initiate translation of cellular mRNA. All positive-strand RNA virus genomes encode RNA-dependent RNA polymerase , a viral protein that synthesizes RNA from an RNA template. Host cell proteins recruited by +ssRNA viruses during replication include RNA-binding proteins , chaperone proteins , and membrane remodeling and lipid synthesis proteins, which collectively participate in exploiting

1260-553: A sister clade in relation to Lenarviricota . The third phylum that contains +ssRNA viruses is Pisuviricota , which has been informally called the "picornavirus supergroup". The phylum contains a large assemblage of eukaryotic viruses known to infect animals, plants, fungi, and protists. The phylum contains three classes, two of which contain only +ssRNA viruses: Pisoniviricetes , which contains nidoviruses , picornaviruses , and sobeliviruses , and Stelpaviricetes , which contains potyviruses and astroviruses . The third class

1344-471: A smaller number of extant viruses showing that the tick-borne viruses emerged from a mosquito-borne group. Several partial and complete genomes of flaviviruses have been found in aquatic invertebrates such as the sea spider Endeis spinosa and several crustaceans and cephalopods. These sequences appear to be related to those in the insect-specific flaviviruses and also the Tamana bat virus groupings. While it

1428-417: A successful global mosquito vector. As mosquito control has failed, several dengue vaccines are in varying stages of development. CYD-TDV, sold under the trade name Dengvaxia, is a tetravalent chimeric vaccine that splices structural genes of the four dengue viruses onto a 17D yellow fever backbone. Dengvaxia is approved in five countries. An alternate approach to the development of flavivirus vaccine vectors

1512-399: A ubiquitin-mediated proteolytic pathway. Caspases are an important group of proteases involved in apoptosis or programmed cell death . The precursors of caspase, procaspase, may be activated by proteolysis through its association with a protein complex that forms apoptosome , or by granzyme B , or via the death receptor pathways. Autoproteolysis takes place in some proteins, whereby

1596-475: Is Duplopiviricetes , whose members are double-stranded RNA viruses that are descended from +ssRNA viruses. Polyprotein Proteolysis in organisms serves many purposes; for example, digestive enzymes break down proteins in food to provide amino acids for the organism, while proteolytic processing of a polypeptide chain after its synthesis may be necessary for the production of an active protein. It

1680-470: Is also important in the regulation of some physiological and cellular processes including apoptosis , as well as preventing the accumulation of unwanted or misfolded proteins in cells. Consequently, abnormality in the regulation of proteolysis can cause disease. Proteolysis can also be used as an analytical tool for studying proteins in the laboratory, and it may also be used in industry, for example in food processing and stain removal. Limited proteolysis of

1764-490: Is based on the use of viruses that infect insects. Insect-specific flaviviruses, such as Binjari virus, are unable to replicate in vertebrate cells. Nevertheless, recombinant viruses in which structural protein genes (prME) of Binjari virus are exchanged with those of dengue virus, Zika virus, West Nile virus, yellow fever virus, or Japanese encephalitis virus replicate efficiently in insect cells where high titers of infectious virus particles are produced. Immunization of mice with

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1848-438: Is consistent with historical records. Kunjin virus diverged from West Nile virus approximately 277 (475–137) years ago. This time corresponds to the settlement of Australia from Europe. The Japanese encephalitis group appears to have evolved in Africa 2000–3000 years ago and then spread initially to South East Asia before migrating to the rest of Asia. Phylogenetic studies of the West Nile virus has shown that it emerged as

1932-402: Is dependent on the presence of a poly-A tail; therefore this process is not host-dependent. Instead, the poly-protein contains an autocatalytic feature which automatically releases the first peptide, a virus specific enzyme. This enzyme is then able to cleave the remaining poly-protein into the individual products. One of the products cleaved is a RNA-dependent RNA polymerase , responsible for

2016-473: Is first synthesized as preproalbumin and contains an uncleaved signal peptide. This forms the proalbumin after the signal peptide is cleaved, and a further processing to remove the N-terminal 6-residue propeptide yields the mature form of the protein. The initiating methionine (and, in bacteria, fMet ) may be removed during translation of the nascent protein. For E. coli , fMet is efficiently removed if

2100-483: Is highly susceptible to this virus, was introduced into this area in the 1930s. In the genus Flavivirus there are 53 defined species: Species and strains sorted by vectors: Mammalian tick-borne virus group Seabird tick-borne virus group The very successful yellow fever 17D vaccine , introduced in 1937, produced dramatic reductions in epidemic activity. Effective inactivated Japanese encephalitis and Tick-borne encephalitis vaccines were introduced in

2184-401: Is largely constant under all physiological conditions. One of the most rapidly degraded proteins is ornithine decarboxylase , which has a half-life of 11 minutes. In contrast, other proteins like actin and myosin have a half-life of a month or more, while, in essence, haemoglobin lasts for the entire life-time of an erythrocyte . The N-end rule may partially determine the half-life of

2268-575: Is left intact. Certain chemicals cause proteolysis only after specific residues, and these can be used to selectively break down a protein into smaller polypeptides for laboratory analysis. For example, cyanogen bromide cleaves the peptide bond after a methionine . Similar methods may be used to specifically cleave tryptophanyl , aspartyl , cysteinyl , and asparaginyl peptide bonds. Acids such as trifluoroacetic acid and formic acid may be used for cleavage. Like other biomolecules, proteins can also be broken down by high heat alone. At 250 °C,

2352-399: Is necessary to break down proteins into small peptides (tripeptides and dipeptides) and amino acids so they can be absorbed by the intestines, and the absorbed tripeptides and dipeptides are also further broken into amino acids intracellularly before they enter the bloodstream. Different enzymes have different specificity for their substrate; trypsin, for example, cleaves the peptide bond after

2436-793: Is not presently clear how aquatic flaviviruses fit into the evolution of this group of viruses, there is some evidence that one of these viruses, Wenzhou shark flavivirus, infects both a crustacean ( Portunus trituberculatus ) Pacific spadenose shark ( Scoliodon macrorhynchos ) shark host, indicating an aquatic arbovirus life cycle. Estimates of divergence times have been made for several of these viruses. The origin of these viruses appears to be at least 9400 to 14,000 years ago. The Old World and New World dengue strains diverged between 150 and 450 years ago. The European and Far Eastern tick-borne encephalitis strains diverged about 1087 (1610–649) years ago. European tick-borne encephalitis and louping ill viruses diverged about 572 (844–328) years ago. This latter estimate

2520-488: Is removed by proteolysis after their transport through a membrane . Some proteins and most eukaryotic polypeptide hormones are synthesized as a large precursor polypeptide known as a polyprotein that requires proteolytic cleavage into individual smaller polypeptide chains. The polyprotein pro-opiomelanocortin (POMC) contains many polypeptide hormones. The cleavage pattern of POMC, however, may vary between different tissues, yielding different sets of polypeptide hormones from

2604-419: Is secreted by the stomach, and is activated only in the acidic environment found in stomach. The pancreas secretes the precursors of a number of proteases such as trypsin and chymotrypsin . The zymogen of trypsin is trypsinogen , which is activated by a very specific protease, enterokinase , secreted by the mucosa of the duodenum . The trypsin, once activated, can also cleave other trypsinogens as well as

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2688-495: Is synthesized as preproinsulin , which yields proinsulin after the signal peptide has been cleaved. The proinsulin is then cleaved at two positions to yield two polypeptide chains linked by two disulfide bonds . Removal of two C-terminal residues from the B-chain then yields the mature insulin. Protein folding occurs in the single-chain proinsulin form which facilitates formation of the ultimate inter-peptide disulfide bonds, and

2772-431: Is the non-neurotropic viruses associated with human haemorrhagic disease. These tend to have Aedes species as vectors and primate hosts. The tick-borne viruses also form two distinct groups: one is associated with seabirds and the other – the tick-borne encephalitis complex viruses – is associated primarily with rodents . The viruses that lack a known vector can be divided into three groups: one closely related to

2856-412: Is then used as a template to create a new positive-sense viral genome. Positive-strand RNA viruses are divided between the phyla Kitrinoviricota , Lenarviricota , and Pisuviricota (specifically classes Pisoniviricetes and Stelpavirictes ) all of which are in the kingdom Orthornavirae and realm Riboviria . They are monophyletic and descended from a common RNA virus ancestor. In

2940-680: The Retroviridae (e.g. HIV ), genome damage appears to be avoided during reverse transcription by strand switching, a form of recombination. Recombination occurs in the Coronaviridae (e.g. SARS ). Recombination in RNA viruses appears to be an adaptation for coping with genome damage. Recombination can also occur infrequently between +ssRNA viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans, as in

3024-708: The Baltimore classification system, +ssRNA viruses belong to Group IV. Positive-sense RNA viruses include pathogens such as the Hepatitis C virus , West Nile virus , dengue virus , and the MERS , SARS , and SARS-CoV-2 coronaviruses , as well as less clinically serious pathogens such as the coronaviruses and rhinoviruses that cause the common cold . Positive-strand RNA virus genomes usually contain relatively few genes, usually between three and ten, including an RNA-dependent RNA polymerase. Coronaviruses have

3108-509: The Flavivirus 5'UTR, a large stem loop (SLA) and a short stem loop (SLB). SLA folds into a Y-shaped structure with a side stem loop and a small top loop. SLA is likely to act as a promoter, and is essential for viral RNA synthesis. SLB is involved in interactions between the 5'UTR and 3'UTR which result in the cyclisation of the viral RNA, which is essential for viral replication. The 3'UTRs are typically 0.3–0.5 kb in length and contain

3192-402: The electron microscope . Most of these viruses are primarily transmitted by the bite from an infected arthropod (mosquito or tick), and hence are classified as arboviruses . Human infections with most of these arboviruses are incidental, as humans are unable to replicate the virus to high enough titers to reinfect the arthropods needed to continue the virus life-cycle – humans are then

3276-459: The peptide bond is cleaved in a self-catalyzed intramolecular reaction . Unlike zymogens , these autoproteolytic proteins participate in a "single turnover" reaction and do not catalyze further reactions post-cleavage. Examples include cleavage of the Asp-Pro bond in a subset of von Willebrand factor type D (VWD) domains and Neisseria meningitidis FrpC self-processing domain, cleavage of

3360-538: The 3'UTR from 5' endonuclease digestion. Nuclease resistance protects the downstream 3' UTR RNA fragment from degradation and is essential for virus-induced cytopathicity and pathogenicity. SL-II has been suggested to contribute to nuclease resistance. It may be related to another hairpin loop identified in the 5'UTR of the Japanese encephalitis virus (JEV) genome. The JEV hairpin is significantly over-represented upon host cell infection and it has been suggested that

3444-615: The Asn-Pro bond in Salmonella FlhB protein, Yersinia YscU protein, as well as cleavage of the Gly-Ser bond in a subset of sea urchin sperm protein, enterokinase, and agrin (SEA) domains. In some cases, the autoproteolytic cleavage is promoted by conformational strain of the peptide bond. Abnormal proteolytic activity is associated with many diseases. In pancreatitis , leakage of proteases and their premature activation in

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3528-531: The N7-methyltransferase and guanylyltransferase activities necessary for forming mature RNA cap structures. RNA binding affinity is reduced by the presence of ATP or GTP and enhanced by S-adenosyl methionine . This protein also encodes a 2′-O methyltransferase. Once translated , the polyprotein is cleaved by a combination of viral and host proteases to release mature polypeptide products. Nevertheless, cellular post-translational modification

3612-564: The XRN1 degrades viral RNA, it stalls at stemloops formed by the secondary structure of the 5' and 3' UTR. This pause results in an undigested fragment of genome RNA known as sfRNA. sfRNA influences the life cycle of the flavivirus in a concentration dependent manner. Accumulation of sfRNA causes (1) antagonization of the cell's innate immune response, thus decreasing host defense against the virus (2) inhibition of XRN1 and Dicer activity to modify RNAi pathways that destroy viral RNA (3) modification of

3696-425: The action of an RNA triphosphatase , with guanylyltransferase , N7- methyltransferase and 2′-O methyltransferase. The virus encodes these activities in its non-structural proteins. The NS3 protein encodes a RNA triphosphatase within its helicase domain. It uses the helicase ATP hydrolysis site to remove the γ-phosphate from the 5′ end of the RNA. The N-terminal domain of the non-structural protein 5 (NS5) has both

3780-478: The apparent descendants of leviviruses, which infect eukaryotes . The phylum is divided into four classes: Leviviricetes , which contains leviviruses and their relatives, Amabiliviricetes , which contains narnaviruses and their relatives, Howeltoviricetes , which contains mitoviruses and their relatives, and Miaviricetes , which contains botourmiaviruses and their relatives. Based on phylogenetic analysis of RdRp, all other RNA viruses are considered to comprise

3864-488: The breaking down of connective tissues in the lung. Other proteases and their inhibitors may also be involved in this disease, for example matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Other diseases linked to aberrant proteolysis include muscular dystrophy , degenerative skin disorders, respiratory and gastrointestinal diseases, and malignancy . Protein backbones are very stable in water at neutral pH and room temperature, although

3948-747: The case of SARS and MERS. Positive-strand RNA viruses are common in plants. In tombusviruses and carmoviruses , RNA recombination occurs frequently during replication. The ability of the RNA-dependent RNA polymerase of these viruses to switch RNA templates suggests a copy choice model of RNA recombination that may be an adaptive mechanism for coping with damage in the viral genome. Other +ssRNA viruses of plants have also been reported to be capable of recombination, such as Brom mosaic bromovirus and Sindbis virus . Positive-strand RNA viruses are found in three phyla: Kitrinoviricota , Lenarviricota , and Pisuviricota , each of which are assigned to

4032-453: The cell's secretory pathway for viral replication. Numerous positive-strand RNA viruses can undergo genetic recombination when at least two viral genomes are present in the same host cell. The capability for recombination among +ssRNA virus pathogens of humans is common. RNA recombination appears to be a major driving force in determining genome architecture and the course of viral evolution among Picornaviridae (e.g. poliovirus). In

4116-496: The disease is not contagious . The known non-arboviruses of the flavivirus family reproduce in either arthropods or vertebrates, but not both, with one odd member of the genus affecting a nematode . Flaviviruses are enveloped and spherical and have icosahedral geometries with a pseudo T=3 symmetry. The virus particle diameter is around 50 nm. Flaviviruses have positive-sense , single-stranded RNA genomes which are non-segmented and around 10–11 kbp in length. In general,

4200-612: The envelope and cell lysis . A G protein-coupled receptor kinase 2 (also known as ADRBK1) appears to be important in entry and replication for several viruses in Flaviviridae . Humans, mammals, mosquitoes, and ticks serve as the natural host. Transmission routes are zoonosis and bite. The positive sense RNA genome of Flavivirus contains 5' and 3' untranslated regions (UTRs). The 5'UTRs are 95–101 nucleotides long in Dengue virus . There are two conserved structural elements in

4284-538: The environment for extracellular digestion whereby proteolytic cleavage breaks proteins into smaller peptides and amino acids so that they may be absorbed and used. In animals the food may be processed extracellularly in specialized organs or guts , but in many bacteria the food may be internalized via phagocytosis . Microbial degradation of protein in the environment can be regulated by nutrient availability. For example, limitation for major elements in proteins (carbon, nitrogen, and sulfur) induces proteolytic activity in

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4368-627: The first known outbreak affected 18 animals in Hungary in 2008. Lineage 1 West Nile virus was detected in South Africa in 2010 in a mare and her aborted fetus ; previously, only lineage 2 West Nile virus had been detected in horses and humans in South Africa. A 2007 fatal case in a killer whale in Texas broadened the known host range of West Nile virus to include cetaceans . Omsk haemorrhagic fever virus appears to have evolved within

4452-546: The fungus Neurospora crassa as well as in of soil organism communities. Proteins in cells are broken into amino acids. This intracellular degradation of protein serves multiple functions: It removes damaged and abnormal proteins and prevents their accumulation. It also serves to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed. The amino acids may then be reused for protein synthesis. The intracellular degradation of protein may be achieved in two ways—proteolysis in lysosome , or

4536-579: The generation and ineffective removal of peptides that aggregate in cells. Proteases may be regulated by antiproteases or protease inhibitors , and imbalance between proteases and antiproteases can result in diseases, for example, in the destruction of lung tissues in emphysema brought on by smoking tobacco. Smoking is thought to increase the neutrophils and macrophages in the lung which release excessive amount of proteolytic enzymes such as elastase , such that they can no longer be inhibited by serpins such as α 1 -antitrypsin , thereby resulting in

4620-411: The genome encodes three structural proteins (Capsid, prM, and Envelope) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5). The genomic RNA is modified at the 5′ end of positive-strand genomic RNA with a cap-1 structure (me-GpppA-me). Flaviviruses replicate in the cytoplasm of the host cells. The genome mimics the cellular mRNA molecule in all aspects except for the absence of

4704-503: The genome of Dengue virus and are found adjacent to each other within the 3'UTR. They appear to be widely conserved across the Flaviviradae. These DB elements have a secondary structure consisting of three helices and they play a role in ensuring efficient translation. Deletion of DB1 has a small but significant reduction in translation but deletion of DB2 has little effect. Deleting both DB1 and DB2 reduced translation efficiency of

4788-461: The hairpin structure may play a role in regulating RNA synthesis. This secondary structure is located within the 3'UTR of the genome of Flavivirus upstream of the DB elements. The function of this conserved structure is unknown but is thought to contribute to ribonuclease resistance. These two conserved secondary structures are also known as pseudo-repeat elements. They were originally identified within

4872-602: The intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules. Flaviviruses are named for the yellow fever virus; the word flavus means 'yellow' in Latin , and yellow fever in turn is named from its propensity to cause yellow jaundice in victims. Flaviviruses share several common aspects: common size (40–65 nm), symmetry ( enveloped , icosahedral nucleocapsid ), nucleic acid ( positive-sense , single-stranded RNA around 10,000–11,000 bases), and appearance under

4956-423: The kingdom Orthornavirae in the realm Riboviria . In the Baltimore classification system, which groups viruses together based on their manner of mRNA synthesis, +ssRNA viruses are group IV. The first +ssRNA phylum is Kitrinoviricota . The phylum contains what have been referred to as the " alphavirus supergroup" and " flavivirus supergroup" along with various other short-genome viruses. Four classes in

5040-506: The largest known RNA genomes, between 27 and 32 kilobases in length, and likely possess replication proofreading mechanisms in the form of an exoribonuclease within nonstructural protein nsp14. Positive-strand RNA viruses have genetic material that can function both as a genome and as messenger RNA ; it can be directly translated into protein in the host cell by host ribosomes . The first proteins to be expressed after infection serve genome replication functions; they recruit

5124-561: The last 1000 years. The viral genomes can be divided into 2 clades — A and B. Clade A has five genotypes, and clade B has one. These clades separated about 700 years ago. This separation appears to have occurred in the Kurgan province. Clade A subsequently underwent division into clade C, D and E 230 years ago. Clade C and E appear to have originated in the Novosibirsk and Omsk Provinces, respectively. The muskrat Ondatra zibethicus , which

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5208-442: The middle of the 20th century. Unacceptable adverse events have prompted change from a mouse-brain inactivated Japanese encephalitis vaccine to safer and more effective second generation Japanese encephalitis vaccines. These may come into wide use to effectively prevent this severe disease in the huge populations of Asia—North, South and Southeast. The dengue viruses produce many millions of infections annually due to transmission by

5292-446: The mosquito-borne viruses, which is associated with bats ; a second, genetically more distant, is also associated with bats; and a third group is associated with rodents. Evolutionary relationships between endogenised viral elements of Flaviviruses and contemporary flaviviruses using maximum likelihood approaches have identified that arthropod-vectored flaviviruses likely emerged from an arachnid source. This contradicts earlier work with

5376-414: The organism, such as its hormonal state as well as nutritional status. In time of starvation, the rate of protein degradation increases. In human digestion , proteins in food are broken down into smaller peptide chains by digestive enzymes such as pepsin , trypsin , chymotrypsin , and elastase , and into amino acids by various enzymes such as carboxypeptidase , aminopeptidase , and dipeptidase . It

5460-467: The pancreas results in the self-digestion of the pancreas . People with diabetes mellitus may have increased lysosomal activity and the degradation of some proteins can increase significantly. Chronic inflammatory diseases such as rheumatoid arthritis may involve the release of lysosomal enzymes into extracellular space that break down surrounding tissues. Abnormal proteolysis may result in many age-related neurological diseases such as Alzheimer 's due to

5544-425: The peptide bond may be easily hydrolyzed, with its half-life dropping to about a minute. Protein may also be broken down without hydrolysis through pyrolysis ; small heterocyclic compounds may start to form upon degradation. Above 500 °C, polycyclic aromatic hydrocarbons may also form, which is of interest in the study of generation of carcinogens in tobacco smoke and cooking at high heat. Proteolysis

5628-461: The peptide bonds in a protein ( acid hydrolysis ). The standard way to hydrolyze a protein or peptide into its constituent amino acids for analysis is to heat it to 105 °C for around 24 hours in 6M hydrochloric acid . However, some proteins are resistant to acid hydrolysis. One well-known example is ribonuclease A , which can be purified by treating crude extracts with hot sulfuric acid so that other proteins become degraded while ribonuclease A

5712-451: The phylum are recognized: Alsuviricetes , the alphavirus supergroup, which contains a large number of plant viruses and arthropod viruses; Flasuviricetes , which contains flaviviruses, Magsaviricetes , which contains nodaviruses and sinhaliviruses ; and Tolucaviricetes , which primarily contains plant viruses. Lenarviricota is the second +ssRNA phylum. It contains the class Leviviricetes , which infect prokaryotes , and

5796-416: The poly-adenylated (poly-A) tail . This feature allows the virus to exploit cellular apparatuses to synthesize both structural and non-structural proteins, during replication . The cellular ribosome is crucial to the replication of the flavivirus, as it translates the RNA, in a similar fashion to cellular mRNA, resulting in the synthesis of a single polyprotein . Cellular RNA cap structures are formed via

5880-412: The positive-sense RNA genome proceeds through double-stranded RNA intermediates, and the purpose of replication in these membranous invaginations may be the avoidance of cellular response to the presence of dsRNA. In many cases subgenomic RNAs are also created during replication. After infection, the entirety of the host cell's translation machinery may be diverted to the production of viral proteins as

5964-581: The positive-strand viral genome to viral replication complexes formed in association with intracellular membranes. These complexes contain proteins of both viral and host cell origin, and may be associated with the membranes of a variety of organelles —often the rough endoplasmic reticulum , but also including membranes derived from mitochondria , vacuoles , the Golgi apparatus , chloroplasts , peroxisomes , plasma membranes , autophagosomal membranes , and novel cytoplasmic compartments. The replication of

6048-417: The precursors of other proteases such as chymotrypsin and carboxypeptidase to activate them. In bacteria, a similar strategy of employing an inactive zymogen or prezymogen is used. Subtilisin , which is produced by Bacillus subtilis , is produced as preprosubtilisin, and is released only if the signal peptide is cleaved and autocatalytic proteolytic activation has occurred. Proteolysis is also involved in

6132-408: The presence of free α-amino group, the negative charge of protein, and the flexibility and stability of the protein. Proteins with larger degrees of intrinsic disorder also tend to have short cellular half-life, with disordered segments having been proposed to facilitate efficient initiation of degradation by the proteasome . The rate of proteolysis may also depend on the physiological state of

6216-448: The protein products of proto-oncogenes, which play central roles in the regulation of cell growth. Cyclins are a group of proteins that activate kinases involved in cell division. The degradation of cyclins is the key step that governs the exit from mitosis and progress into the next cell cycle . Cyclins accumulate in the course the cell cycle, then abruptly disappear just before the anaphase of mitosis. The cyclins are removed via

6300-475: The rate of hydrolysis of different peptide bonds can vary. The half life of a peptide bond under normal conditions can range from 7 years to 350 years, even higher for peptides protected by modified terminus or within the protein interior. The rate of hydrolysis however can be significantly increased by extremes of pH and heat. Spontaneous cleavage of proteins may also involve catalysis by zinc on serine and threonine. Strong mineral acids can readily hydrolyse

6384-449: The regulation of many cellular processes by activating or deactivating enzymes, transcription factors, and receptors, for example in the biosynthesis of cholesterol, or the mediation of thrombin signalling through protease-activated receptors . Some enzymes at important metabolic control points such as ornithine decarboxylase is regulated entirely by its rate of synthesis and its rate of degradation. Other rapidly degraded proteins include

6468-458: The same polyprotein. Many viruses also produce their proteins initially as a single polypeptide chain that were translated from a polycistronic mRNA. This polypeptide is subsequently cleaved into individual polypeptide chains. Common names for the polyprotein include gag ( group-specific antigen ) in retroviruses and ORF1ab in Nidovirales . The latter name refers to the fact that

6552-476: The second residue is small and uncharged, but not if the second residue is bulky and charged. In both prokaryotes and eukaryotes , the exposed N-terminal residue may determine the half-life of the protein according to the N-end rule . Proteins that are to be targeted to a particular organelle or for secretion have an N-terminal signal peptide that directs the protein to its final destination. This signal peptide

6636-400: The synthesis of a negative-sense RNA molecule. Consequently, this molecule acts as the template for the synthesis of the genomic progeny RNA. Flavivirus genomic RNA replication occurs on rough endoplasmic reticulum membranes in membranous compartments. New viral particles are subsequently assembled. This occurs during the budding process which is also responsible for the accumulation of

6720-445: The ultimate intra-peptide disulfide bond, found in the native structure of insulin. Proteases in particular are synthesized in the inactive form so that they may be safely stored in cells, and ready for release in sufficient quantity when required. This is to ensure that the protease is activated only in the correct location or context, as inappropriate activation of these proteases can be very destructive for an organism. Proteolysis of

6804-563: The viral genome to 25%. CRE is the Cis-acting replication element, also known as the 3'SL RNA elements, and is thought to be essential in viral replication by facilitating the formation of a "replication complex". Although evidence has been presented for an existence of a pseudoknot structure in this RNA, it does not appear to be well conserved across flaviviruses. Deletions of the 3' UTR of flaviviruses have been shown to be lethal for infectious clones. A conserved hairpin (cHP) structure

6888-688: The viral replication complex to increase viral reproduction. Overall, sfRNA is implied in multiple pathways that compromise host defenses and promote infection by flaviviruses. The flaviviruses can be divided into two clades: one with vector-borne viruses and the other with no known vector. The vector clade, in turn, can be subdivided into a mosquito-borne clade and a tick-borne clade. These groups can be divided again. The mosquito group can be divided into two branches: one branch contains neurotropic viruses, often associated with encephalitic disease in humans or livestock. This branch tends to be spread by Culex species and to have bird reservoirs. The second branch

6972-439: The zymogen yields an active protein; for example, when trypsinogen is cleaved to form trypsin , a slight rearrangement of the protein structure that completes the active site of the protease occurs, thereby activating the protein. Proteolysis can, therefore, be a method of regulating biological processes by turning inactive proteins into active ones. A good example is the blood clotting cascade whereby an initial event triggers

7056-486: Was later found in several Flavivirus genomes and is thought to direct translation of capsid proteins. It is located just downstream of the AUG start codon . Subgenomic flavivirus RNA (sfRNA) is an extension of the 3' UTR and has been demonstrated to play a role in flavivirus replication and pathogenesis. sfRNA is produced by incomplete degradation of genomic viral RNA by the host cells 5'-3' exoribonuclease 1 (XRN1). As

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