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45-396: 22227 ENSG00000109424 ENSMUSG00000031710 P25874 P12242 NM_021833 NM_009463 NP_068605 NP_033489 Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1 ) is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis , and makes
90-452: A Beta-3 adrenergic receptor on the plasma membrane . This activates adenylyl cyclase , which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A , causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase , thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding
135-415: A completely aliphatic side chain. Multiple prolines and/or hydroxyprolines in a row can create a polyproline helix , the predominant secondary structure in collagen . The hydroxylation of proline by prolyl hydroxylase (or other additions of electron-withdrawing substituents such as fluorine ) increases the conformational stability of collagen significantly. Hence, the hydroxylation of proline
180-407: A hydrogen bond acceptor. Peptide bond formation with incoming Pro-tRNA in the ribosome is considerably slower than with any other tRNAs, which is a general feature of N -alkylamino acids. Peptide bond formation is also slow between an incoming tRNA and a chain ending in proline; with the creation of proline-proline bonds slowest of all. The exceptional conformational rigidity of proline affects
225-543: A kinetic standpoint, cis – trans proline isomerization is a very slow process that can impede the progress of protein folding by trapping one or more proline residues crucial for folding in the non-native isomer, especially when the native protein requires the cis isomer. This is because proline residues are exclusively synthesized in the ribosome as the trans isomer form. All organisms possess prolyl isomerase enzymes to catalyze this isomerization, and some bacteria have specialized prolyl isomerases associated with
270-444: A potential endogenous excitotoxin . In plants , proline accumulation is a common physiological response to various stresses but is also part of the developmental program in generative tissues (e.g. pollen ). A diet rich in proline was linked to an increased risk of depression in humans in a study from 2022 that was tested on a limited pre-clinical trial on humans and primarily in other organisms. Results were significant in
315-457: A quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio. UCP1 belongs to the UCP family which are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into
360-426: A role in normal physiology, as in cold exposure or hibernation , because the energy is used to generate heat (see thermogenesis ) instead of producing ATP . Some plants species use the heat generated by uncoupling proteins for special purposes. Eastern skunk cabbage , for example, keeps the temperature of its spikes as much as 20 °C higher than the environment, spreading odor and attracting insects that fertilize
405-486: A role in regulating calcium concentrations in this region. Considering calcium ions play a large role in neurotransmission, scientists predict that these UCPs directly affect neurotransmission. As discussed above, neurons in the hippocampus experience increased concentrations of ATP in the presence of these uncoupling proteins. This leads scientists to hypothesize that UCPs improve synaptic plasticity and transmission. Proline Proline (symbol Pro or P )
450-447: Is a critical biochemical process for maintaining the connective tissue of higher organisms. Severe diseases such as scurvy can result from defects in this hydroxylation, e.g., mutations in the enzyme prolyl hydroxylase or lack of the necessary ascorbate (vitamin C) cofactor. Peptide bonds to proline, and to other N -substituted amino acids (such as sarcosine ), are able to populate both
495-402: Is an osmoprotectant and therefore is used in many pharmaceutical and biotechnological applications. The growth medium used in plant tissue culture may be supplemented with proline. This can increase growth, perhaps because it helps the plant tolerate the stresses of tissue culture. For proline's role in the stress response of plants, see § Biological activity . Proline is one of
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#1732854919877540-405: Is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins ), although it does not contain the amino group -NH 2 but is rather a secondary amine . The secondary amine nitrogen is in the protonated form (NH 2 ) under biological conditions, while the carboxyl group is in the deprotonated −COO form. The "side chain" from the α carbon connects to
585-399: Is based on the similar ANT mechanism. The substrate comes in to the half open UCP1 protein from the cytoplasmic side of the membrane, the protein closes the cytoplasmic side so the substrate is enclosed in the protein, and then the matrix side of the protein opens, allowing the substrate to be released into the mitochondrial matrix . The opening and closing of the protein is accomplished by
630-567: Is not possible for these knockout mice, indicating that UCP1 is an essential driver of heat production in these brown adipose tissues. Elsewhere in the body, uncoupling protein activities are known to affect the temperature in micro-environments. This is believed to affect other proteins' activity in these regions, though work is still required to determine the true consequences of uncoupling-induced temperature gradients within cells. The structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy. The structure has
675-414: Is reduced to proline by pyrroline-5-carboxylate reductase (using NADH or NADPH), or turned into ornithine by ornithine aminotransferase , followed by cyclisation by ornithine cyclodeaminase to form proline. L -Proline has been found to act as a weak agonist of the glycine receptor and of both NMDA and non-NMDA ( AMPA / kainate ) ionotropic glutamate receptors . It has been proposed to be
720-561: Is supported by independent studies which show increased ROS production in both UCP2 and UCP3 knockout mice. This process is important to human health, as high-concentrations of ROS are believed to be involved in the development of degenerative diseases. By detecting the associated mRNA , UCP2, UCP4, and UCP5 were shown to reside in neurons throughout the human central nervous system. These proteins play key roles in neuronal function. While many study findings remain controversial, several findings are widely accepted. For example, UCPs alter
765-493: The cis and trans isomers. Most peptide bonds overwhelmingly adopt the trans isomer (typically 99.9% under unstrained conditions), chiefly because the amide hydrogen ( trans isomer) offers less steric repulsion to the preceding C α atom than does the following C α atom ( cis isomer). By contrast, the cis and trans isomers of the X-Pro peptide bond (where X represents any amino acid) both experience steric clashes with
810-405: The secondary structure of proteins near a proline residue and may account for proline's higher prevalence in the proteins of thermophilic organisms. Protein secondary structure can be described in terms of the dihedral angles φ, ψ and ω of the protein backbone. The cyclic structure of proline's side chain locks the angle φ at approximately −65°. Proline acts as a structural disruptor in
855-426: The 1960s investigating brown adipose tissue , found that in addition to producing more heat than typical of other tissues, brown adipose tissue seemed to short circuit, or uncouple, respiration coupling. Uncoupling protein 1 was discovered in 1976 by David G. Nicholls , Vibeke Bernson , and Gillian Heaton , and the discovery was published in 1978 and shown to be the protein responsible for this uncoupling effect. UCP1
900-430: The ancestor of modern vertebrates, show that this gene was passed on to all modern vertebrates, but aside from placental mammals, none have heat producing capability. This further suggests that UCP1 had a different original purpose and in fact phylogenetic and sequence analyses indicate that UCP1 is likely a mutated form of a dicarboxylate carrier protein that adapted for thermogenesis in placental mammals. Researchers in
945-887: The combined concentration of ADP and ATP, actually resulting in a net increase in ATP concentration when these uncoupling proteins become coupled (i.e. the mechanism to allow proton leaking is inhibited). The entire list of functions of UCP2 and UCP3 is not known. However, studies indicate that these proteins are involved in a negative-feedback loop limiting the concentration of reactive oxygen species (ROS). Current scientific consensus states that UCP2 and UCP3 perform proton transportation only when activation species are present. Among these activators are fatty acids, ROS, and certain ROS byproducts that are also reactive. Therefore, higher levels of ROS directly and indirectly cause increased activity of UCP2 and UCP3. This, in turn, increases proton leak from
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#1732854919877990-694: The cytoplasmic or matrix state. The atomic structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy. The structure has the typical fold of a member of the SLC25 family. UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak. UCP1 is expressed in brown adipose tissue, which is functionally found only in eutherians . The UCP1, or thermogenin, gene likely arose in an ancestor of modern vertebrates , but did not initially allow for our vertebrate ancestor to use non-shivering thermogenesis for warmth. It wasn't until heat generation
1035-445: The flowers. However, other substances, such as 2,4-dinitrophenol and carbonyl cyanide m-chlorophenyl hydrazone , also serve the same uncoupling function. Salicylic acid is also an uncoupling agent (chiefly in plants) and will decrease production of ATP and increase body temperature if taken in extreme excess. Uncoupling proteins are increased by thyroid hormone , norepinephrine , epinephrine , and leptin . Scientists observed
1080-439: The free calcium concentrations in the neuron. Mitochondria are a major site of calcium storage in neurons, and the storage capacity increases with potential across mitochondrial membranes. Therefore, when the uncoupling proteins reduce potential across these membranes, calcium ions are released to the surrounding environment in the neuron. Due to the high concentrations of mitochondria near axon terminals , this implies UCPs play
1125-509: The homologs. The homologs are as follows: The first uncoupling protein discovered, UCP1, was discovered in the brown adipose tissues of hibernators and small rodents, which provide non-shivering heat to these animals. These brown adipose tissues are essential to maintaining the body temperature of small rodents, and studies with (UCP1)- knockout mice show that these tissues do not function correctly without functioning uncoupling proteins. In fact, these studies revealed that cold-acclimation
1170-458: The inhibition caused by purine nucleotides ( GDP and ADP ). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state. UCP1 is very similar to the ATP/ADP Carrier protein, or Adenine Nucleotide Translocator ( ANT ). The proposed alternating access model for UCP1
1215-429: The intermembrane space to return to the mitochondrial matrix and hence dissipating the proton gradient. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits
1260-436: The middle of regular secondary structure elements such as alpha helices and beta sheets ; however, proline is commonly found as the first residue of an alpha helix and also in the edge strands of beta sheets . Proline is also commonly found in turns (another kind of secondary structure), and aids in the formation of beta turns. This may account for the curious fact that proline is usually solvent-exposed, despite having
1305-442: The mitochondria, lowering the proton-motive force across mitochondrial membranes, activating the electron transport chain. Limiting the proton motive force through this process results in a negative feedback loop that limits ROS production. Especially, UCP2 decreases the transmembrane potential of mitochondria, thus decreasing the production of ROS. Thus, cancer cells may increase the production of UCP2 in mitochondria. This theory
1350-412: The mitochondrial intermembrane space. The energy lost in dissipating the proton gradient via UCPs is not used to do biochemical work. Instead, heat is generated. This is what links UCP to thermogenesis. However, not every type of UCPs are related to thermogenesis. Although UCP2 and UCP3 are closely related to UCP1, UCP2 and UCP3 do not affect thermoregulatory abilities of vertebrates. UCPs are positioned in
1395-475: The neighboring substitution and have a much lower energy difference. Hence, the fraction of X-Pro peptide bonds in the cis isomer under unstrained conditions is significantly elevated, with cis fractions typically in the range of 3-10%. However, these values depend on the preceding amino acid, with Gly and aromatic residues yielding increased fractions of the cis isomer. Cis fractions up to 40% have been identified for aromatic–proline peptide bonds. From
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1440-404: The nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid . It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L - glutamate . It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG). Proline is the only proteinogenic amino acid which is a secondary amine , as the nitrogen atom is attached both to
1485-413: The other organisms. The distinctive cyclic structure of proline's side chain gives proline an exceptional conformational rigidity compared to other amino acids. It also affects the rate of peptide bond formation between proline and other amino acids. When proline is bound as an amide in a peptide bond, its nitrogen is not bound to any hydrogen, meaning it cannot act as a hydrogen bond donor, but can be
1530-488: The ribosome. However, not all prolines are essential for folding, and protein folding may proceed at a normal rate despite having non-native conformers of many X–Pro peptide bonds. Proline and its derivatives are often used as asymmetric catalysts in proline organocatalysis reactions. The CBS reduction and proline catalysed aldol condensation are prominent examples. In brewing, proteins rich in proline combine with polyphenols to produce haze (turbidity). L -Proline
1575-483: The same membrane as the ATP synthase , which is also a proton channel. The two proteins thus work in parallel with one generating heat and the other generating ATP from ADP and inorganic phosphate, the last step in oxidative phosphorylation . Mitochondria respiration is coupled to ATP synthesis (ADP phosphorylation), but is regulated by UCPs. UCPs belong to the mitochondrial carrier (SLC25) family. Uncoupling proteins play
1620-464: The synthesis of proline from phthalimide propylmalonic ester. The name proline comes from pyrrolidine , one of its constituents. Proline is biosynthetically derived from the amino acid L - glutamate . Glutamate-5-semialdehyde is first formed by glutamate 5-kinase (ATP-dependent) and glutamate-5-semialdehyde dehydrogenase (which requires NADH or NADPH). This can then either spontaneously cyclize to form 1-pyrroline-5-carboxylic acid , which
1665-617: The thermogenic activity in brown adipose tissue , which eventually led to the discovery of UCP1, initially known as "Uncoupling Protein". The brown tissue revealed elevated levels of mitochondria respiration and another respiration not coupled to ATP synthesis, which symbolized strong thermogenic activity. UCP1 was the protein discovered responsible for activating a proton pathway that was not coupled to ADP phosphorylation (ordinarily done through ATP Synthase ). There are five UCP homologs known in mammals. While each of these performs unique functions, certain functions are performed by several of
1710-522: The tightening and loosening of salt bridges at the membrane surface of the protein. Substantiation for this modelling of UCP1 on ANT is found in the many conserved residues between the two proteins that are actively involved in the transportation of substrate across the membrane. Both proteins are integral membrane proteins , localized to the inner mitochondrial membrane, and they have a similar pattern of salt bridges, proline residues, and hydrophobic or aromatic amino acids that can close or open when in
1755-452: The translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix . UCP1 is restricted to brown adipose tissue , where it provides a mechanism for the enormous heat-generating capacity of the tissue. UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids are released by the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto
1800-442: The treatment of obesity, due to their ability to dissipate excess metabolic stores. Uncoupling protein An uncoupling protein ( UCP ) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH -powered pumping of protons from the mitochondrial matrix to
1845-425: The two amino acids that do not follow along with the typical Ramachandran plot , along with glycine . Due to the ring formation connected to the beta carbon, the ψ and φ angles about the peptide bond have fewer allowable degrees of rotation. As a result, it is often found in "turns" of proteins as its free entropy (Δ S ) is not as comparatively large to other amino acids and thus in a folded form vs. unfolded form,
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1890-598: The typical fold of a member of the SLC25 family. UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner. The effect of UCP2 and UCP3 on ATP concentrations varies depending on cell type. For example, pancreatic beta cells experience a decrease in ATP concentration with increased activity of UCP2. This is associated with cell degeneration, decreased insulin secretion, and type II diabetes. Conversely, UCP2 in hippocampus cells and UCP3 in muscle cells stimulate production of mitochondria . The larger number of mitochondria increases
1935-458: The α-carbon and to a chain of three carbons that together form a five-membered ring. Proline was first isolated in 1900 by Richard Willstätter who obtained the amino acid while studying N -methylproline, and synthesized proline by the reaction of sodium salt of diethyl malonate with 1,3-dibromopropane . The next year, Emil Fischer isolated proline from casein and the decomposition products of γ-phthalimido-propylmalonic ester, and published
1980-708: Was adaptively selected for in placental mammal descendants of this common ancestor that UCP1 evolved its current function in brown adipose tissue to provide additional warmth. While UCP1 plays a key thermogenic role in wide range placental mammals, particularly those with small body size and those that hibernate, the UCP1 gene has lost functionality in several large-bodied lineages (e.g. horses , elephants , sea cows , whales and hyraxes ) and lineages with low metabolic rates (e.g. pangolins , armadillos , sloths and anteaters ). Recent discoveries of non-heat-generating orthologues of UCP1 in fish and marsupials , other descendants of
2025-571: Was later purified for the first time in 1980 and was first cloned in 1988. Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3 , UCP4 , and UCP5 (also known as BMCP1 or SLC25A14). Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into
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