Complement component 1s
Complement component 1s is a protein involved in the complement system. C1s is part of the C1 complex. In humans, it is encoded by the C1S gene. C1s cleaves C4 and C2, which leads to the production of the classical pathway C3-convertase. C1q - another part of the C1 complex C1r - another part of the C1 complex MASP-2 - a protein similar to C1s, part of the lectin pathway Complement+C1s at the US National Library of Medicine Medical Subject Headings Human C1S genome location and C1S gene details page in the UCSC Genome Browser
Factor D a protein which in humans is encoded by the CFD gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B; the protein encoded by this gene is a member of the trypsin family of peptidases. The encoded protein is a component of the alternative complement pathway best known for its role in humoral suppression of infectious agents; this protein is a serine protease, secreted by adipocytes into the bloodstream. The encoded protein has a high level of expression in fat, suggesting a role for adipose tissue in immune system biology. Factor D is a serine protease that stimulates glucose transport for triglyceride accumulation in fats cells and inhibits lipolysis; the level of Factor D is decreased in the obese, this reduction may be due to high activity or resistance but exact cause is not known. All members of the chymotrypsin family of serine proteases have similar structures. In all cases, including factor D, there are two antiparallel β-barrel domains with each barrel containing six β-strands with the same typology in all enzymes.
The major difference in backbone structure between Factor D and the other serine proteases of the chymotrpsin family is in the surface loops connecting the secondary structural elements. Factor D displays different conformations of major catalytic and substrate-binding residues found in the chrotrypsin family; these features suggest the catalytic activity of factor D is prohibited unless conformational changes are induced by a realignment. Complement+Factor+D at the US National Library of Medicine Medical Subject Headings This article incorporates text from the United States National Library of Medicine, in the public domain
Leucine is an essential amino acid, used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group, an α-carboxylic acid group, a side chain isobutyl group, making it a non-polar aliphatic amino acid, it is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, beans and other legumes, it is encoded by the codons UUA, UUG, CUU, CUC, CUA, CUG. Like valine and isoleucine, leucine is a branched-chain amino acid; the primary metabolic end products of leucine metabolism are acetoacetate. It is the most important ketogenic amino acid in humans.p. 101Leucine and β-hydroxy β-methylbutyric acid, a minor leucine metabolite, exhibit pharmacological activity in humans and have been demonstrated to promote protein biosynthesis via the phosphorylation of the mechanistic target of rapamycin. As a food additive, L-leucine is classified as a flavor enhancer.
The Food and Nutrition Board of the U. S. Institute of Medicine set Recommended Dietary Allowances for essential amino acids in 2002. For leucine, for adults 19 years and older, 42 mg/kg body weight/day; as a dietary supplement, leucine has been found to slow the degradation of muscle tissue by increasing the synthesis of muscle proteins in aged rats. However, results of comparative studies are conflicted. Long-term leucine supplementation does not increase muscle strength in healthy elderly men. More studies are needed, preferably ones based on an random sample of society. Factors such as lifestyle choices, gender, exercise, etc. must be factored into the analyses to isolate the effects of supplemental leucine as a standalone, or if taken with other branched chain amino acids. Until dietary supplemental leucine cannot be associated as the prime reason for muscular growth or optimal maintenance for the entire population. Both L-leucine and D-leucine protect mice against seizures. D-leucine terminates seizures in mice after the onset of seizure activity, at least as as diazepam and without sedative effects.
Decreased dietary intake of L-leucine promotes adiposity in mice. High blood levels of leucine are associated with insulin resistance in humans and rodents; this might be due to the effect of leucine to stimulate mTOR signaling. Dietary restriction of leucine and the other BCAAs can reverse diet-induced obesity in wild-type mice by increasing energy expenditure, can restrict fat mass gain of hyperphagic rats. Leucine toxicity, as seen in decompensated maple syrup urine disease, causes delirium and neurologic compromise, can be life-threatening. A high intake of leucine may cause or exacerbate symptoms of pellagra in people with low niacin status because it interferes with the conversion of L-tryptophan to niacin. Leucine at a dose exceeding 500 mg/kg/d was observed with hyperammonemia; as such, unofficially, a tolerable upper intake level for leucine in healthy adult men can be suggested at 500 mg/kg/d or 35 g/d under acute dietary conditions. Leucine is a dietary amino acid with the capacity to directly stimulate myofibrillar muscle protein synthesis.
This effect of leucine arises results from its role as an activator of the mechanistic target of rapamycin, a serine-threonine protein kinase that regulates protein biosynthesis and cell growth. The activation of mTOR by leucine is mediated through Rag GTPases, leucine binding to leucyl-tRNA synthetase, leucine binding to sestrin 2, other mechanisms. Leucine metabolism occurs in many tissues in the human body. Adipose and muscle tissue use leucine in the formation of other compounds. Combined leucine use in these two tissues is seven times greater than in the liver. In healthy individuals 60% of dietary L-leucine is metabolized after several hours, with 5% of dietary L-leucine being converted to β-hydroxy β-methylbutyric acid. Around 40% of dietary L-leucine is converted to acetyl-CoA, subsequently used in the synthesis of other compounds; the vast majority of L-leucine metabolism is catalyzed by the branched-chain amino acid aminotransferase enzyme, producing α-ketoisocaproate. Α-KIC is metabolized by the mitochondrial enzyme branched-chain α-ketoacid dehydrogenase, which converts it to isovaleryl-CoA.
Isovaleryl-CoA is subsequently metabolized by isovaleryl-CoA dehydrogenase and converted to MC-CoA, used in the synthesis of acetyl-CoA and other compounds. During biotin deficiency, HMB can be synthesized from MC-CoA via enoyl-CoA hydratase and an unknown thioesterase enzyme, which convert MC-CoA into HMB-CoA and HMB-CoA into HMB respectively. A small amount of α-KIC is metabolized in the liver by the cytosolic enzyme 4-hydroxyphenylpyruvate dioxygenase, which converts α-KIC to HMB. In healthy individuals, this minor pathway – which involves the conversion of L-leucine to α-KIC and HMB – is the predominant route of HMB synthesis. A small fraction of L-leucine metabolism – less than 5% in all tissues except the testes where it accounts for about 33% – is catalyzed by leucine aminomutase, producing β-leucine, subsequently metabolized into β-ketoisocaproate, β-ketoisocaproyl-CoA, acetyl-CoA by a series of uncharacterized enzymes; the metabolism o
Complement membrane attack complex
The membrane attack complex or terminal complement complex is a structure formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, as such is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane channels; these channels disrupt the cell membrane of target cells, leading to death. Active MAC is composed of the subunits C5b, C7, C8 and several C9 molecules. A number of proteins participate in the assembly of the MAC. Freshly activated C5b binds to C6 to form a C5b-6 complex to C7 forming the C5b-6-7 complex; the C5b-6-7 complex binds to C8, composed of three chains, thus forming the C5b-6-7-8 complex. C5b-6-7-8 subsequently binds to C9 and acts as a catalyst in the polymerization of C9. MAC is composed of a complex of four complement proteins that bind to the outer surface of the plasma membrane, many copies of a fifth protein that hook up to one another, forming a ring in the membrane. C6-C9 all contain a common MACPF domain.
This region is homologous to cholesterol-dependent cytolysins from Gram-positive bacteria. The ring structure formed by C9 is a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive. If the pre-MAC complexes of C5b-7, C5b-8 or C5b-9 do not insert into a membrane, they can form inactive complexes with Protein S; these fluid phase complexes do not bind to cell membranes and are scavenged by clusterin and vitronectin, two regulators of complement. The membrane attack complex is initiated when the complement protein C5 convertase cleaves C5 into C5a and C5b. All three pathways of the complement system initiate the formation of MAC. Another complement protein, C6, binds to C5b; the C5bC6 complex is bound by C7. This junction alters the configuration of the protein molecules exposing a hydrophobic site on C7 that allows the C7 to insert into the phospholipid bilayer of the pathogen. Similar hydrophobic sites on C8 and C9 molecules are exposed when they bind to the complex, so they can insert into the bilayer.
C8 is a complex made of C8 alpha-gamma. C8 alpha-gamma has the hydrophobic area. C8 alpha-gamma induces the polymerization of 10-16 molecules of C9 into a pore-forming structure known as the membrane attack complex. MAC has a hydrophobic external face allowing it to associate with the lipid bilayer. MAC has a hydrophilic internal face to allow the passage of water. Multiple molecules of C9 can join spontaneously in concentrated solution to form polymers of C9; these polymers can form a tube-like structure. CD59 acts to inhibit the complex; this exists on body cells to protect them from MAC. A rare condition, paroxysmal nocturnal haemoglobinuria, results in red blood cells that lack CD59; these cells can, therefore, be lysed by MAC. Deficiencies of C5 to C9 components does not lead to generic infections, but only to increased susceptibility to Neisseria spp. since these bacteria have a thick cell wall and glycocalix. Terminal complement pathway deficiency Perforin Pore-forming toxin Media related to Complement membrane attack complex at Wikimedia Commons Complement+Membrane+Attack+Complex at the US National Library of Medicine Medical Subject Headings
An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors, they are used in pesticides. Not all molecules; the binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. Inhibitor binding is either irreversible. Irreversible inhibitors react with the enzyme and change it chemically; these inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both. Many drug molecules are enzyme inhibitors, so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is judged by its specificity and its potency. A high specificity and potency ensure.
Enzyme inhibitors occur and are involved in the regulation of metabolism. For example, enzymes in a metabolic pathway can be inhibited by downstream products; this type of negative feedback slows the production line when products begin to build up and is an important way to maintain homeostasis in a cell. Other cellular enzyme inhibitors are proteins that bind to and inhibit an enzyme target; this can help control enzymes that may be damaging like proteases or nucleases. A well-characterised example of this is the ribonuclease inhibitor, which binds to ribonucleases in one of the tightest known protein–protein interactions. Natural enzyme inhibitors can be poisons and are used as defences against predators or as ways of killing prey. Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions and ionic bonds. Multiple weak bonds between the inhibitor and the active site combine to produce strong and specific binding. In contrast to substrates and irreversible inhibitors, reversible inhibitors do not undergo chemical reactions when bound to the enzyme and can be removed by dilution or dialysis.
There are four kinds of reversible enzyme inhibitors. They are classified according to the effect of varying the concentration of the enzyme's substrate on the inhibitor. In competitive inhibition, the substrate and inhibitor cannot bind to the enzyme at the same time, as shown in the figure on the right; this results from the inhibitor having an affinity for the active site of an enzyme where the substrate binds. This type of inhibition can be overcome by sufficiently high concentrations of substrate, i.e. by out-competing the inhibitor. However, the apparent Km will increase as it takes a higher concentration of the substrate to reach the Km point, or half the Vmax. Competitive inhibitors are similar in structure to the real substrate. In uncompetitive inhibition, the inhibitor binds only to the substrate-enzyme complex; this type of inhibition causes Vmax to Km to decrease. In non-competitive inhibition, the binding of the inhibitor to the enzyme reduces its activity but does not affect the binding of substrate.
As a result, the extent of inhibition depends only on the concentration of the inhibitor. Vmax will decrease due to the inability for the reaction to proceed as efficiently, but Km will remain the same as the actual binding of the substrate, by definition, will still function properly. In mixed inhibition, the inhibitor can bind to the enzyme at the same time as the enzyme's substrate. However, the binding of the inhibitor affects the binding of the substrate, vice versa; this type of inhibition can be reduced, but not overcome by increasing concentrations of substrate. Although it is possible for mixed-type inhibitors to bind in the active site, this type of inhibition results from an allosteric effect where the inhibitor binds to a different site on an enzyme. Inhibitor binding to this allosteric site changes the conformation of the enzyme so that the affinity of the substrate for the active site is reduced. Reversible inhibition can be described quantitatively in terms of the inhibitor's binding to the enzyme and to the enzyme-substrate complex, its effects on the kinetic constants of the enzyme.
In the classic Michaelis-Menten scheme below, an enzyme binds to its substrate to form the enzyme–substrate complex ES. Upon catalysis, this complex breaks down to release free enzyme; the inhibitor can bind to ES with the dissociation constants Ki or Ki', respectively. When an enzyme has multiple substrates, inhibitors can show different types of inhibition depending on which substrate is considered; this results from the active site containing two different binding sites within the active site, one for each substrate. For example, an inhibitor might compete with
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a soluble glycoprotein that circulates in human plasma, its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, decay accelerating activity against the alternative pathway C3-convertase, C3bBb. Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses; this is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification.
The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans and or sialic acids that are present on host cells but not on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces. The molecule is made up of 20 complement control protein modules connected to one another by short linkers and arranged in an extended head to tail fashion; each of the CCP modules consists of around 60 amino acids with four cysteine residues disulfide bonded in a 1-3 2-4 arrangement, a hydrophobic core built around an invariant tryptophan residue. The CCP modules are numbered from 1-20. To date atomic structures have been determined for CCPs 1-3, CCP 5, CCP 7, CCPs 10-11 and CCPs 11-12, CCPs 12-13, CCP 15, CCP 16, CCPs 15-16, CCPs 18-20, CCPs 19-20; the atomic structure for CCPs 6-8 bound to the GAG mimic sucrose octasulfate, CCPs 1-4 in complex with C3b and CCPs 19-20 in complex with C3d have been determined. Although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution.
Information available to date indicates that CCP modules 1-4 is responsible for the cofactor and decay acceleration activities of factor H, whereas self/non-self discrimination occurs predominantly through GAG binding to CCP modules 7 and/or GAG or sialic acid binding to 19-20. Due to the central role that factor H plays in the regulation of complement, there are a number of clinical implications arising from aberrant factor H activity. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections. Underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases, it is not surprising therefore that mutations or single nucleotide polymorphisms in factor H result in pathologies. Moreover, the complement inhibitory activities of factor H, other complement regulators, are used by pathogens to increase virulence, it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene.
Homozygous individuals have an sevenfold increased chance of developing age-related macular degeneration, while heterozygotes have a two-to-threefold increased likelihood of developing the disease. This SNP, located in CCP module 7 of factor H, has been shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease. Deletion of two adjacent genes with a high degree of homology to complement factor H, named complement factor H-related 3 and complement factor H-related 1, protects against age-related macular degeneration because of reduced competition for binding of CFH to vascular surface binding sites. Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the alternative complement pathway in patients with schizophrenia, it was investigated functional single nucleotide polymorphisms of gene encoding factor H, found CFH rs424535 SNP was positively associated with schizophrenia, so rs424535*A minor allele of the CFH gene may represent a risk factor for schizophrenia.
It was found that rs800292 SNP was positively associated with stroke and rs800912 minor allele of the CFH gene might be considered as a risk factor for ischemic stroke. Haemolytic uraemic syndrome is a disease associated with microangiopathic haemolytic anemia and acute renal failure. A rare subset of this disease, has been linked to mutations in genes of the complement system, with the factor H mutations being the most numerous; these factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin and C3d binding. Given the central role of factor H in protecting cells from complement, it is
Classical complement pathway
The classical complement pathway is one of three pathways which activate the complement system, part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM. Following activation, a series of proteins are recruited to generate C3 convertase, which cleaves the C3 protein; the C3b component of the cleaved C3 binds to C3 convertase to generate C5 convertase, which cleaves the C5 protein. The cleaved products attract phagocytes to the site of infection and tags target cells for elimination by phagocytosis. In addition, the C5 convertase initiates the terminal phase of the complement system, leading to the assembly of the membrane attack complex; the membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and death. The classical complement pathway can be activated by apoptotic cells, necrotic cells, acute phase proteins; the classical pathway is distinct from the other complement pathways in its unique activation triggers and cascade sequence.
Activation of the complement pathway through the classical, lectin or alternative complement pathway is followed by a cascade of reactions leading to the membrane attack complex. The classical complement pathway can be initiated by the binding of antigen-antibody complexes to the C1q protein; the globular regions of C1q recognize and bind to the Fc region of antibody isotypes IgG or IgM. These globular regions of C1q can bind to bacterial and viral surface proteins, apoptotic cells, acute phase proteins. In the absence of these activation factors, C1q is part of the inactive C1 complex which consists of six molecules of C1q, two molecules of C1r, two molecules of C1s; the binding of C1q leads to conformational the activation of the serine protease C1r. The activated C1r cleaves and activates the serine protease C1s; the activated C1s cleaves C4 into C4a and C4b, C2 into C2a and C2b. The larger fragments C4b and C2b form C4b2b, a C3 convertase of the classical pathway. C3 convertase cleaves C3 into C3a and C3b.
While the anaphylatoxin C3a interacts with its C3a receptor to recruit leukocytes, C3b contributes to further downstream complement activation. C3b binds to the C3 convertase. C5 convertase cleaves C5 into C5a and C5b. Like C3a, C5a is an anaphylatoxin with interacts with its cognate C5a receptor to attract leukocytes. Subsequent interactions between C5b and other terminal components C6, C7, C8, C9 form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing; because of its role in the innate immune system classical complement has been implicated in a number of pathogen related disorders. Complement is responsible for immune inflammatory response in adipose tissues, implicated in the development of obesity. Obesity in turn results in an abnormally high level of complement activation via production of the c1 component of the classical pathway, which can lead to tissue inflammation and insulin resistance, however the exact mechanisms that causes this is yet unknown.
Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via classical complement activation. This process involves creating synthetic peptides that target conserved regions in HIV specific proteins and induce an antibody specific immune response through IgG antibodies; this is important for targeting the virus in its intracellular phase because the antibodies specific to the synthetic peptides can trigger the classical complement pathway and induce the death of HIV infected cells. Classical complement activation has been shown to combat Methicillin-resistant Staphylococcus aureus. Certain variants of the IgM antibody were found to bind the Methicillin-resistant Staphylococcus aureus these IgM were found to be critical in complement activation through the classical pathway and subsequent destruction of the bacteria. Therapies that utilize classical complement activation have been shown to be effective in targeting and killing cancer cells and destroying tumors.
Tachyplesin, a small peptide, has been shown to exhibit these effects. When injected into target tissue encourages recruitment of C1q and activates downstream events leading to the formation of the C5b-9 complex which damages tumor cells, killing them. Lack of regulation of the classical complement pathway through the deficiency in C1-inhibitor results in episodic angioedema. C1-inhibitor defiency can be acquired, resulting in hereditary or acquired angioedema. C1-inhibitor plays the role of inactivating C1r and C1s to prevent further downstream classical complement activity. C1-inhibitor controls the processes involved in maintaining vascular permeability; as a result, C1-inhibitor levels of less than 50% of the standard lead to increased vascular permeability, characteristic of angioedema. Cinryze, a human plasma derived C1-esterase inhibitor, has been approved for use in 2008 for the prevention of hereditary angioedema attacks. Deficiency in the C1q protein of the classical complement pathway can lead to development of systemic lupus erythematosus.
Among the many functions of C1q, C1q triggers clearance of immune complexes and apoptotic cells by activating the classical pathway and binding directly onto phagocytes. Systemic lupus erythematosus from insufficient amounts of C1q is characterized by the accumulation of autoantibodies and apoptotic cells. Studies are being done to look into antibodies against C1q as a diagnostic marker for systemic lupus erythematosus. Alternative complement pathway – another complement system p