Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which are the basic units of information for DNA, it represents about 8% of the total DNA in human cells. It was the last completed chromosome, sequenced two decades after the beginning of the Human Genome Project; the following are some of the gene count estimates of human chromosome 1. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 1. For complete list, see the link in the infobox on the right. DENN1B hypothesized to be related to asthma Partial list of the genes located on p-arm of human chromosome 1: Partial list of the genes located on q-arm of human chromosome 1: There are 890 known diseases related to this chromosome.
Some of these diseases are hearing loss, Alzheimer's disease and breast cancer. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, in regions where no function is evident. Complete monosomy is invariably lethal before birth. Complete trisomy is lethal within days after conception; some partial deletions and partial duplications produce birth defects. The following diseases are some of those related to genes on chromosome 1: National Institutes of Health. "Chromosome 1". Genetics Home Reference. Retrieved 2017-05-06. "Final genome'chapter' published". BBC NEWS. 2006-05-18. Retrieved 2017-05-06. "Chromosome 1". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
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
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People have two copies of this chromosome. Chromosome 3 spans 200 million base pairs and represents about 6.5 percent of the total DNA in cells. The following are some of the gene count estimates of human chromosome 3; because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 3. For complete list, see the link in the infobox on the right. Partial list of the genes located on p-arm of human chromosome 3: Partial list of the genes located on q-arm of human chromosome 3: The following diseases and disorders are some of those related to genes on chromosome 3: National Institutes of Health. "Chromosome 3".
Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 3". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
A cofactor is a non-protein chemical compound or metallic ion, required for an enzyme's activity. Cofactors can be considered "helper molecules"; the rates at which these happen are characterized by enzyme kinetics. Cofactors can be subclassified as either inorganic ions or complex organic molecules called coenzymes, the latter of, derived from vitamins and other organic essential nutrients in small amounts. A coenzyme, or covalently bound is termed a prosthetic group. Cosubstrates are transiently bound to the protein and will be released at some point get back in; the prosthetic groups, on the other hand, are bound permanently to the protein. Both of them have the same function, to facilitate the reaction of enzymes and protein. Additionally, some sources limit the use of the term "cofactor" to inorganic substances. An inactive enzyme without the cofactor is called an apoenzyme, while the complete enzyme with cofactor is called a holoenzyme; some enzymes or enzyme complexes require several cofactors.
For example, the multienzyme complex pyruvate dehydrogenase at the junction of glycolysis and the citric acid cycle requires five organic cofactors and one metal ion: loosely bound thiamine pyrophosphate, covalently bound lipoamide and flavin adenine dinucleotide, cosubstrates nicotinamide adenine dinucleotide and coenzyme A, a metal ion. Organic cofactors are vitamins or made from vitamins. Many contain the nucleotide adenosine monophosphate as part of their structures, such as ATP, coenzyme A, FAD, NAD+; this common structure may reflect a common evolutionary origin as part of ribozymes in an ancient RNA world. It has been suggested that the AMP part of the molecule can be considered to be a kind of "handle" by which the enzyme can "grasp" the coenzyme to switch it between different catalytic centers. Cofactors can be divided into two major groups: organic Cofactors, such as flavin or heme, inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+, or iron-sulfur clusters. Organic cofactors are sometimes further divided into prosthetic groups.
The term coenzyme refers to enzymes and, as such, to the functional properties of a protein. On the other hand, "prosthetic group" emphasizes the nature of the binding of a cofactor to a protein and, refers to a structural property. Different sources give different definitions of coenzymes and prosthetic groups; some consider bound organic molecules as prosthetic groups and not as coenzymes, while others define all non-protein organic molecules needed for enzyme activity as coenzymes, classify those that are bound as coenzyme prosthetic groups. These terms are used loosely. A 1980 letter in Trends in Biochemistry Sciences noted the confusion in the literature and the arbitrary distinction made between prosthetic groups and coenzymes group and proposed the following scheme. Here, cofactors were defined as an additional substance apart from protein and substrate, required for enzyme activity and a prosthetic group as a substance that undergoes its whole catalytic cycle attached to a single enzyme molecule.
However, the author could not arrive at a single all-encompassing definition of a "coenzyme" and proposed that this term be dropped from use in the literature. Metal ions are common cofactors; the study of these cofactors falls under the area of bioinorganic chemistry. In nutrition, the list of essential trace elements reflects their role as cofactors. In humans this list includes iron, manganese, copper and molybdenum. Although chromium deficiency causes impaired glucose tolerance, no human enzyme that uses this metal as a cofactor has been identified. Iodine is an essential trace element, but this element is used as part of the structure of thyroid hormones rather than as an enzyme cofactor. Calcium is another special case, in that it is required as a component of the human diet, it is needed for the full activity of many enzymes, such as nitric oxide synthase, protein phosphatases, adenylate kinase, but calcium activates these enzymes in allosteric regulation binding to these enzymes in a complex with calmodulin.
Calcium is, therefore, a cell signaling molecule, not considered a cofactor of the enzymes it regulates. Other organisms require additional metals as enzyme cofactors, such as vanadium in the nitrogenase of the nitrogen-fixing bacteria of the genus Azotobacter, tungsten in the aldehyde ferredoxin oxidoreductase of the thermophilic archaean Pyrococcus furiosus, cadmium in the carbonic anhydrase from the marine diatom Thalassiosira weissflogii. In many cases, the cofactor includes both an organic component. One diverse set of examples is the heme proteins, which consist of a porphyrin ring coordinated to iron. Iron-sulfur clusters are complexes of iron and sulfur atoms held within proteins by cysteinyl residues, they play both structural and functional roles, including electron transfer, redox sensing, as structural modules. Organic cofactors are small organic molecules that can be either loosely or bound to the enzyme and directly participate in the reaction. In the latter case, when it is difficult to remove without denaturing the enzyme, it can be called a prosthetic group.
It is important to emphasize that there is no sharp division between loosely and bound cofactors. Indeed, many such as NAD+ can be bound in some enzymes, while it is loosely bound in others. Another example is thiamine pyrophosphate, bound in transketolase or pyruvate decarboxylase, while it is less tightly
In molecular biology, the protein domain Saccharopine dehydrogenase named Saccharopine reductase, is an enzyme involved in the metabolism of the amino acid lysine, via an intermediate substance called saccharopine. The Saccharopine dehydrogenase enzyme can be classified under EC 188.8.131.52, EC 184.108.40.206, EC 220.127.116.11, EC 18.104.22.168. It has an important function in lysine metabolism and catalyses a reaction in the alpha-Aminoadipic acid pathway; this pathway is unique to fungal organisms therefore, this molecule could be useful in the search for new antibiotics. This protein family includes saccharopine dehydrogenase and homospermidine synthase, it is found in prokaryotes and archaea. Simplistically, SDH uses NAD+ as an oxidant to catalyse the reversible pyridine nucleotide dependent oxidative deamination of the substrate, Saccharopine, in order to form the products and alpha-ketoglutarate; this can be described by the following equation: SDHSaccharopine ⇌ lysine + alpha-ketoglutarate Saccharopine dehydrogenase EC catalyses the condensation to of l-alpha-aminoadipate-delta-semialdehyde with l-glutamate to give an imine, reduced by NADPH to give saccharopine.
In some organisms this enzyme is found as a bifunctional polypeptide with lysine ketoglutarate reductase. Homospermidine synthase proteins. Homospermidine synthase catalyses the synthesis of the polyamine homospermidine from 2 mol putrescine in an NAD+-dependent reaction. There appears to be two protein domains of similar size. One domain is a Rossmann fold that binds NAD+/NADH, the other is similar. Both domains contain a six-stranded parallel beta-sheet surrounded by loops. Deficiencies are associated with hyperlysinemia. Saccharopine+Dehydrogenases at the US National Library of Medicine Medical Subject Headings
Branched-chain alpha-keto acid dehydrogenase complex
The branched-chain α-ketoacid dehydrogenase complex is a multi-subunit complex of enzymes, found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-chain alpha-ketoacids. BCKDC is a member of the mitochondrial α-ketoacid dehydrogenase complex family comprising pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, key enzymes that function in the Krebs cycle; this complex requires the following 5 coenzymes: Thiamine pyrophosphate Lipoate Coenzyme A Flavin adenine dinucleotide Nicotinamide adenine dinucleotide In animal tissue, BCKDC catalyzes an irreversible step in the catabolism of the branched-chain amino acids L-isoleucine, L-valine, L-leucine, acting on their deaminated derivatives. In bacteria, this enzyme participates in the synthesis of long-chain fatty acids. In plants, this enzyme is involved in the synthesis of long-chain hydrocarbons; the overall catabolic reaction catalyzed by the BCKDC is shown in Figure 1.
The mechanism of enzymatic catalysis by the BCKDC draws upon the elaborate structure of this large enzyme complex. This enzyme complex is composed of three catalytic components: alpha-ketoacid dehydrogenase, dihydrolipoyl transacylase, dihydrolipoamide dehydrogenase. In humans, 24 copies of E2 arranged in octahedral symmetry form the core of the BCKDC. Non-covalently linked to this polymer of 24 E2 subunits are 12 E1 α2β2 tetramers and 6 E3 homodimers. In addition to the E1/E3-binding domain, there are 2 other important structural domains in the E2 subunit: a lipoyl-bearing domain in the amino-terminal portion of the protein and an inner-core domain in the carboxy-terminal portion; the inner-core domain is linked to the other two domains of the E2 subunit by two interdomain segments. The inner-core domain is necessary to form the oligomeric core of the enzyme complex and catalyzes the acyltransferase reaction; the lipoyl domain of E2 is free to swing between the active sites of the E1, E2, E3 subunits on the assembled BCKDC by virtue of the conformational flexibility of the aforementioned linkers.
Thus, in terms of function as well as structure, the E2 component plays a central role in the overall reaction catalyzed by the BCKDC. The role of each subunit is as follows: E1 uses thiamine pyrophosphate as a catalytic cofactor. E1 catalyzes both the decarboxylation of the α-ketoacid and the subsequent reductive acylation of the lipoyl moiety, covalently bound to E2. E2 catalyzes a transfer of the acyl group from the lipoyl moiety to coenzyme A; the E3 component is a flavoprotein, it re-oxidizes the reduced lipoyl sulfur residues of E2 using FAD as the oxidant. FAD transfers these protons and electrons to NAD+ to complete the reaction cycle; as mentioned, BCKDC’s primary function in mammals is to catalyze an irreversible step in the catabolism of branched-chain amino acids. However, the BCKDC has a broad specificity oxidizing 4-methylthio-2-oxobutyrate and 2-oxobutyrate at comparable rates and with similar Km values as for its branched-chain amino acid substrates; the BCKDC will oxidize pyruvate, but at such a slow rate this side reaction has little physiological significance.
The reaction mechanism is. Please note that any of several branched-chain α-ketoacids could have been used as a starting material. NOTE: Steps 1 and 2 occur in the E1 domainSTEP 1: α-ketoisovalerate combines with TPP and is decarboxylated; the proper arrow-pushing mechanism is shown in Figure 3. STEP 2: The 2-methylpropanol-TPP is oxidized to form an acyl group while being transferred to the lipoyl cofactor on E2. Note that TPP is regenerated; the proper arrow-pushing mechanism is shown in Figure 4. NOTE: The acylated lipoyl arm now leaves E1 and swings into the E2 active site, where Step 3 occurs. STEP 3: Acyl group transfer to CoA; the proper arrow-pushing mechanism is shown in Figure 5. *NOTE: The reduced lipoyl arm now swings into the E3 active site, where Steps 4 and 5 occur. STEP 4: Oxidation of the lipoyl moiety by the FAD coenzyme, as shown in Figure 6. STEP 5: Reoxidation of FADH2 to FAD, producing NADH: FADH2 + NAD+ --> FAD + NADH + H+ A deficiency in any of the enzymes of this complex as well as an inhibition of the complex as a whole leads to a buildup of branched-chain amino acids and their harmful derivatives in the body.
These accumulations lend a sweet smell to bodily excretions, leading to a pathology known as maple syrup urine disease. This enzyme is an autoantigen recognized in primary biliary cirrhosis, a form of acute liver failure; these antibodies appear to recognize oxidized protein that has resulted from inflammatory immune responses. Some of these inflammatory responses are explained by gluten sensitivity. Other mitochondrial autoantigens include pyruvate dehydrogenase and branched-chain oxoglutarate dehydrogenase, which are antigens recognized by anti-mitochondrial antibodies. GeneReviews/NCBI/NIH/UW entry on Maple Syrup Urine Disease Branched+Chain+Ketoacid+Dehydrogenase at the US National Library of Medicine Medical Subject Headings EC 22.214.171.124
Metabolism is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; these enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, respond to their environments.. Metabolic reactions may be categorized as catabolic - the breaking down of compounds. Catabolism releases energy, anabolism consumes energy; the chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts - they allow a reaction to proceed more - and they allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.
The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals; the basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions. A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants; these similarities in metabolic pathways are due to their early appearance in evolutionary history, their retention because of their efficacy. Most of the structures that make up animals and microbes are made from three basic classes of molecule: amino acids and lipids; as these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion.
These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life. Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds. Many proteins are enzymes. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape. Proteins are important in cell signaling, immune responses, cell adhesion, active transport across membranes, the cell cycle. Amino acids contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress. Lipids are the most diverse group of biochemicals, their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. Lipids are defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform.
The fats are a large group of compounds that contain fatty glycerol. Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, hydrophilic groups such as phosphate as in phospholipids. Steroids such as cholesterol are another major class of lipids. Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, fill numerous roles, such as the storage and transport of energy and structural components; the basic carbohydrate units are called monosaccharides and include galactose and most glucose. Monosaccharides can be linked together to form polysaccharides in limitless ways; the two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group, attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, its interpretation through the processes of transcription and protein biosynthesis.
This information is propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome. RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made