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112-402: ADME, describes the disposition of a pharmaceutical compound within an organism . The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug . Sometimes, liberation and/or toxicity are also considered, yielding LADME, ADMET, or LADMET. For a compound to reach

224-466: A futile cycle . Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate ; plants do, but animals do not, have the necessary enzymatic machinery. As a result, after long-term starvation, vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as

336-440: 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 by attaching a nucleobase to a ribose sugar. These bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines . Nucleotides also act as coenzymes in metabolic-group-transfer reactions. Metabolism involves

448-475: A complex. Distribution can be a serious problem at some natural barriers like the blood–brain barrier . Compounds begin to break down as soon as they enter the body. The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes, termed cytochrome P450 enzymes. As metabolism occurs, the initial (parent) compound is converted to new compounds called metabolites . When metabolites are pharmacologically inert, metabolism deactivates

560-423: A constant set of conditions within cells, a condition called homeostasis . Metabolic regulation also allows organisms to respond to signals and interact actively with their environments. Two closely linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly,

672-429: A cycle of reactions that add the acyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an alkane group. The enzymes of fatty acid biosynthesis are divided into two groups: in animals and fungi, all these fatty acid synthase reactions are carried out by a single multifunctional type I protein, while in plant plastids and bacteria separate type II enzymes perform each step in

784-421: A form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is the object of pharmacokinetics . Metabolism is one of the stages (see ADME ) of the drug's transit through

896-519: A group of people who acetylate slowly ( slow acetylators ) and those who acetylate quickly ( rapid acetylators ), split roughly 50:50 in the population of Canada. However, variability in NAT2 alleles distribution across different populations is high and some ethnicities have higher proportion of slow acetylators. This variation in metabolising capacity may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. NAT2 enzyme

1008-458: A hydrogen acceptor. Hundreds of separate types of dehydrogenases remove electrons from their substrates and reduce NAD into NADH. This reduced form of the coenzyme is then a substrate for any of the reductases in the cell that need to transfer hydrogen atoms to their substrates. Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD /NADH form is more important in catabolic reactions, while NADP /NADPH

1120-470: A large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important classes of this group is that of the glutathione S-transferases (GSTs). After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates. Here,

1232-558: A large group of compounds that contain fatty acids and glycerol ; a glycerol molecule attached to three fatty acids by ester linkages is called a triacylglyceride . Several variations of the basic structure exist, including backbones such as sphingosine in sphingomyelin , and hydrophilic groups such as phosphate in phospholipids . Steroids such as sterol 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

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1344-404: A larger increase in the entropy of their environments. The metabolism of a cell achieves this by coupling the spontaneous processes of catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by creating disorder. As the environments of most organisms are constantly changing, the reactions of metabolism must be finely regulated to maintain

1456-472: A membrane. Pumping protons out of the mitochondria creates a proton concentration difference across the membrane and generates an electrochemical gradient . This force drives protons back into the mitochondrion through the base of an enzyme called ATP synthase . The flow of protons makes the stalk subunit rotate, causing the active site of the synthase domain to change shape and phosphorylate adenosine diphosphate —turning it into ATP. Chemolithotrophy

1568-553: A molecule of formaldehyde , while oxidation of the O-methyl groups takes place to a lesser extent. Cytochrome P450 reductase, also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase The general scheme of electron flow in

1680-482: A pharmacologically inactive compound (a prodrug ) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one ( toxification ). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts acetonitrile to HOCH 2 CN, which rapidly dissociates into formaldehyde and hydrogen cyanide . Phase I metabolism of drug candidates can be simulated in

1792-591: A set of xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases , UDP-glucuronosyltransferases , and glutathione S -transferases . This system of enzymes acts in three stages to firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further metabolized before being excreted (phase III). In ecology , these reactions are particularly important in microbial biodegradation of pollutants and

1904-459: A short ancestral pathway, the duplication and then divergence of entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction pathway. The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step fashion with novel functions created from pre-existing steps in

2016-530: A source of energy, while switching between carbon fixation and the fermentation of organic compounds. In many organisms, the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves the storage of energy as a proton concentration gradient. This proton motive force then drives ATP synthesis. The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic reaction centres . Reaction centers are classified into two types depending on

2128-401: A tissue, it usually must be taken into the bloodstream – often via mucous surfaces like the digestive tract ( intestinal absorption) – before being taken up by the target cells. Factors such as poor compound solubility, gastric emptying time, intestinal transit time, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug

2240-413: A vast array of chemical reactions, but most fall under a few basic types of reactions that involve the transfer of functional groups of atoms and their bonds within molecules. This common chemistry allows cells to use a small set of metabolic intermediates to carry chemical groups between different reactions. These group-transfer intermediates are called coenzymes . Each class of group-transfer reactions

2352-419: Is oxidative stress . Here, processes including oxidative phosphorylation and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen peroxide . These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes such as catalases and peroxidases . Living organisms must obey the laws of thermodynamics , which describe

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2464-855: Is a crucial pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction ) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true, as in enzyme inhibition . However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can accelerate this conversion and increase drug levels, potentially causing toxicity. Various physiological and pathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g., pharmacogenetics ), enterohepatic circulation , nutrition , sex differences or gut microbiota . This last factor has significance because gut microorganisms are able to chemically modify

2576-489: Is a primary metaboliser of antituberculosis ( isoniazid ), some antihypertensive ( hydralazine ), anti-arrythmic drugs ( procainamide ), antidepressants ( phenelzine ) and many more and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomenons of altered metabolism due to inherited variations have been described for other drug-metabolising enzymes, like CYP2D6 , CYP3A4 , DPYD , UGT1A1 . DPYD and UGT1A1 genotyping

2688-571: Is a type of metabolism found in prokaryotes where energy is obtained from the oxidation of inorganic compounds . These organisms can use hydrogen , reduced sulfur compounds (such as sulfide , hydrogen sulfide and thiosulfate ), ferrous iron (Fe(II)) or ammonia as sources of reducing power and they gain energy from the oxidation of these compounds. These microbial processes are important in global biogeochemical cycles such as acetogenesis , nitrification and denitrification and are critical for soil fertility . The energy in sunlight

2800-419: Is absorbed after oral administration. Absorption critically determines the compound's bioavailability . Drugs that absorb poorly when taken orally must be administered in some less desirable way, like intravenously or by inhalation (e.g. zanamivir ). Routes of administration are an important consideration. The compound needs to be carried to its effector site, most often via the bloodstream. From there,

2912-401: Is an organic compound needed in small quantities that cannot be made in cells. In human nutrition , most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated or are coupled to nucleotides when they are used in cells. Nicotinamide adenine dinucleotide (NAD ), a derivative of vitamin B 3 ( niacin ), is an important coenzyme that acts as

3024-446: Is called gluconeogenesis . Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis . However, this pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is important as it allows the formation and breakdown of glucose to be regulated separately, and prevents both pathways from running simultaneously in

3136-409: Is captured by plants , cyanobacteria , purple bacteria , green sulfur bacteria and some protists . This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis, which is discussed below. The energy capture and carbon fixation systems can, however, operate separately in prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as

3248-405: Is carried out by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that consume it. These coenzymes are therefore continuously made, consumed and then recycled. One central coenzyme is adenosine triphosphate (ATP), the energy currency of cells. This nucleotide is used to transfer chemical energy between different chemical reactions. There

3360-638: Is carried out by the enzyme RuBisCO as part of the Calvin–Benson cycle . Three types of photosynthesis occur in plants, C3 carbon fixation , C4 carbon fixation and CAM photosynthesis . These differ by the route that carbon dioxide takes to the Calvin cycle, with C3 plants fixing CO 2 directly, while C4 and CAM photosynthesis incorporate the CO 2 into other compounds first, as adaptations to deal with intense sunlight and dry conditions. In photosynthetic prokaryotes

3472-485: Is composed of a phosphate attached to a ribose or deoxyribose sugar group which is attached to a nitrogenous base . Nucleic acids are critical for the storage and use of genetic information, and its interpretation through the processes of transcription and protein biosynthesis . This information is protected by DNA repair mechanisms and propagated through DNA replication . Many viruses have an RNA genome , such as HIV , which uses reverse transcription to create

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3584-477: Is its primary structure . Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP -dependent reaction carried out by an aminoacyl tRNA synthetase . This aminoacyl-tRNA

3696-635: Is likely due to their efficacy . In various diseases, such as type II diabetes , metabolic syndrome , and cancer , normal metabolism is disrupted. The metabolism of cancer cells is also different from the metabolism of normal cells, and these differences can be used to find targets for therapeutic intervention in cancer. Most of the structures that make up animals, plants and microbes are made from four basic classes of molecules : amino acids , carbohydrates , nucleic acid and lipids (often called fats ). As these molecules are vital for life, metabolic reactions either focus on making these molecules during

3808-559: Is needed, or back to glucose in the Cori cycle . An alternative route for glucose breakdown is the pentose phosphate pathway , which produces less energy but supports anabolism (biomolecule synthesis). This pathway reduces the coenzyme NADP to NADPH and produces pentose compounds such as ribose 5-phosphate for synthesis of many biomolecules such as nucleotides and aromatic amino acids . Fats are catabolized by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and

3920-786: Is now required before administration of the corresponding substrate compounds ( 5-FU and capecitabine for DPYD and irinotecan for UGT1A1) to determine the activity of DPYD and UGT1A1 enzyme and reduce the dose of the drug in order to avoid severe adverse reactions. Dose, frequency, route of administration, tissue distribution and protein binding of the drug affect its metabolism. Pathological factors can also influence drug metabolism, including liver , kidney , or heart diseases. In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. This can be used to identify individuals most at risk from adverse reaction. Studies on how people transform

4032-475: Is only a small amount of ATP in cells, but as it is continuously regenerated, the human body can use about its own weight in ATP per day. ATP acts as a bridge between catabolism and anabolism . Catabolism breaks down molecules, and anabolism puts them together. Catabolic reactions generate ATP, and anabolic reactions consume it. It also serves as a carrier of phosphate groups in phosphorylation reactions. A vitamin

4144-411: Is produced in response to rises in blood glucose levels . Binding of the hormone to insulin receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into storage molecules such as fatty acids and glycogen . The metabolism of glycogen is controlled by activity of phosphorylase , the enzyme that breaks down glycogen, and glycogen synthase ,

4256-546: Is scarce, or when cells undergo metabolic stress. Lipids are the most diverse group of biochemicals. Their main structural uses are as part of internal and external biological membranes , such as the cell membrane . Their chemical energy can also be used. Lipids contain a long, non-polar hydrocarbon chain with a small polar region containing oxygen. Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as ethanol , benzene or chloroform . The fats are

4368-487: Is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal metabolism . The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems. All organisms use cell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and

4480-479: Is the metabolic breakdown of drugs by living organisms , usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic pathways that modify the chemical structure of xenobiotics , which are compounds foreign to an organism's normal biochemistry, such as any drug or poison . These pathways are

4592-617: 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 likely due to their early appearance in evolutionary history , and their retention

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4704-421: Is the most important site and it is where products are excreted through urine. Biliary excretion or fecal excretion is the process that initiates in the liver and passes through to the gut until the products are finally excreted along with waste products or feces. The last main method of excretion is through the lungs (e.g. anesthetic gases). Excretion of drugs by the kidney involves 3 main mechanisms: Sometimes,

4816-422: Is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for

4928-422: Is the synthesis of carbohydrates from sunlight and carbon dioxide (CO 2 ). In plants, cyanobacteria and algae, oxygenic photosynthesis splits water, with oxygen produced as a waste product. This process uses the ATP and NADPH produced by the photosynthetic reaction centres , as described above, to convert CO 2 into glycerate 3-phosphate , which can then be converted into glucose. This carbon-fixation reaction

5040-495: Is then a substrate for the ribosome , which joins the amino acid onto the elongating protein chain, using the sequence information in a messenger RNA . Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of metabolic energy. Consequently, most organisms have efficient systems to salvage preformed nucleotides. Purines are synthesized as nucleosides (bases attached to ribose ). Both adenine and guanine are made from

5152-423: 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 and 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 rapidly—and they also allow

5264-429: Is used in anabolic reactions. Inorganic elements play critical roles in metabolism; some are abundant (e.g. sodium and potassium ) while others function at minute concentrations. About 99% of a human's body weight is made up of the elements carbon , nitrogen , calcium , sodium , chlorine , potassium , hydrogen , phosphorus , oxygen and sulfur . Organic compounds (proteins, lipids and carbohydrates) contain

5376-417: The first pass effect . Other sites of drug metabolism include epithelial cells of the gastrointestinal tract , lungs , kidneys , and the skin . These sites are usually responsible for localized toxicity reactions. The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 monooxygenase system

5488-426: The bioremediation of contaminated land and oil spills. Many of these microbial reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even persistent organic pollutants such as organochloride compounds. A related problem for aerobic organisms

5600-499: The chloroplast . These protons move back through the membrane as they drive the ATP synthase, as before. The electrons then flow through photosystem I and can then be used to reduce the coenzyme NADP . This coenzyme can enter the Calvin cycle or be recycled for further ATP generation. Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to synthesize complex molecules. In general,

5712-467: The control exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux through the pathway). For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control of the pathway. There are multiple levels of metabolic regulation. In intrinsic regulation,

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5824-441: The cytoskeleton , a system of scaffolding that maintains the cell shape. Proteins are also important in cell signaling , immune responses , cell adhesion , active transport across membranes, and the cell cycle . Amino acids also contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle ( tricarboxylic acid cycle ), especially when a primary source of energy, such as glucose ,

5936-492: The glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides . Drug metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase enzymes such as glutathione S-transferases. Finally, in phase III,

6048-406: The last universal common ancestor . This universal ancestral cell was prokaryotic and probably a methanogen that had extensive amino acid, nucleotide, carbohydrate and lipid metabolism. The retention of these ancient pathways during later evolution may be the result of these reactions having been an optimal solution to their particular metabolic problems, with pathways such as glycolysis and

6160-550: The mevalonate pathway produces these compounds from acetyl-CoA, while in plants and bacteria the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates. One important reaction that uses these activated isoprene donors is sterol biosynthesis . Here, the isoprene units are joined to make squalene and then folded up and formed into a set of rings to make lanosterol . Lanosterol can then be converted into other sterols such as cholesterol and ergosterol . Organisms vary in their ability to synthesize

6272-426: 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

6384-407: The stomach and pancreas , and in salivary glands . The amino acids or sugars released by these extracellular enzymes are then pumped into cells by active transport proteins. Carbohydrate catabolism is the breakdown of carbohydrates into smaller units. Carbohydrates are usually taken into cells after they have been digested into monosaccharides such as glucose and fructose . Once inside,

6496-477: The γ-glutamate and glycine residues in the glutathione molecule are removed by gamma-glutamyl transpeptidase and dipeptidases . In the final step, the cysteine residue in the conjugate is acetylated . Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein (MRP) family. These proteins are members of

6608-428: The 20 common amino acids. Most bacteria and plants can synthesize all twenty, but mammals can only synthesize eleven nonessential amino acids, so nine essential amino acids must be obtained from food. Some simple parasites , such as the bacteria Mycoplasma pneumoniae , lack all amino acid synthesis and take their amino acids directly from their hosts. All amino acids are synthesized from intermediates in glycolysis,

6720-1036: The POR/P450 system is: NADPH → FAD → FMN → P450 → O 2 During reduction reactions, a chemical can enter futile cycling , in which it gains a free-radical electron, then promptly loses it to oxygen (to form a superoxide anion ). In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate , glycine , or glucuronic acid . Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH 2 ), and thiol (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produce active metabolites . The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported. These reactions are catalysed by

6832-431: The actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions . These pathways are also important in environmental science , with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation , or persist in the environment. The enzymes of xenobiotic metabolism, particularly

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6944-508: The administered dose of parent drug and this usually reduces the effects on the body. Metabolites may also be pharmacologically active, sometimes more so than the parent drug (see prodrug ). Compounds and their metabolites need to be removed from the body via excretion , usually through the kidneys (urine) or in the feces. Unless excretion is complete, accumulation of foreign substances can adversely affect normal metabolism. There are three main sites where drug excretion occurs. The kidney

7056-413: The body that involves the breakdown of the drug so that it can be excreted by the body. The metabolism of pharmaceutical drugs is an important aspect of pharmacology and medicine . For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer , and

7168-431: The brain that cannot metabolize fatty acids. In other organisms such as plants and bacteria, this metabolic problem is solved using the glyoxylate cycle , which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of acetyl-CoA to oxaloacetate , where it can be used for the production of glucose. Other than fat, glucose is stored in most tissues, as an energy resource available within

7280-439: The cell for energy. M. tuberculosis can also grow on the lipid cholesterol as a sole source of carbon, and genes involved in the cholesterol-use pathway(s) have been validated as important during various stages of the infection lifecycle of M. tuberculosis . Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide to produce energy. The oxidation pathway starts with

7392-441: The citric acid cycle producing their end products highly efficiently and in a minimal number of steps. The first pathways of enzyme-based metabolism may have been parts of purine nucleotide metabolism, while previous metabolic pathways were a part of the ancient RNA world . Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These include the sequential addition of novel enzymes to

7504-416: The citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and glutamine . Nonessensial amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then transaminated to form an amino acid. Amino acids are made into proteins by being joined in a chain of peptide bonds . Each different protein has a unique sequence of amino acid residues: this

7616-637: The coenzyme nicotinamide adenine dinucleotide (NAD ) into NADH. Macromolecules cannot be directly processed by cells. Macromolecules must be broken into smaller units before they can be used in cell metabolism. Different classes of enzymes are used to digest these polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside hydrolases that digest polysaccharides into simple sugars known as monosaccharides . Microbes simply secrete digestive enzymes into their surroundings, while animals only secrete these enzymes from specialized cells in their guts , including

7728-534: The complex molecules that make up cellular structures are constructed step-by-step from smaller and simpler precursors. Anabolism involves three basic stages. First, the production of precursors such as amino acids , monosaccharides , isoprenoids and nucleotides , secondly, their activation into reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as proteins , polysaccharides , lipids and nucleic acids . Anabolism in organisms can be different according to

7840-566: The compound may distribute into muscle and organs, usually to differing extents. After entry into the systemic circulation, either by intravascular injection or by absorption from any of the various extracellular sites, the drug is subjected to numerous distribution processes that tend to lower its plasma concentration. Distribution is defined as the reversible transfer of a drug between one compartment to another. Some factors affecting drug distribution include regional blood flow rates, molecular size, polarity and binding to serum proteins, forming

7952-479: The conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted . The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification systems

8064-488: The construction of cells and tissues, or on breaking them down and using them to obtain energy, by their digestion. These biochemicals can be joined to make polymers such as DNA and proteins , essential macromolecules of life. Proteins are made of amino acids arranged in a linear chain joined by peptide bonds . Many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form

8176-422: The conversion of food to building blocks of proteins , lipids , nucleic acids , and some carbohydrates ; and the elimination of metabolic wastes . These enzyme -catalyzed reactions allow organisms to grow and reproduce, maintain their structures , and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and

8288-445: The electrons removed from organic molecules in areas such as the citric acid cycle are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of proteins in the membranes of mitochondria called the electron transport chain . In prokaryotes , these proteins are found in the cell's inner membrane . These proteins use the energy from reduced molecules like NADH to pump protons across

8400-683: The end of the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage proteins such as ferritin or metallothionein when not in use. Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by anabolic reactions which build molecules. The exact nature of these catabolic reactions differ from organism to organism, and organisms can be classified based on their sources of energy, hydrogen, and carbon (their primary nutritional groups ), as shown in

8512-469: The enzyme that makes it. These enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the phosphorylation of these enzymes. The central pathways of metabolism described above, such as glycolysis and the citric acid cycle, are present in all three domains of living things and were present in

8624-650: The exchange of electrolytes between the extracellular fluid and the cell's fluid, the cytosol . Electrolytes enter and leave cells through proteins in the cell membrane called ion channels . For example, muscle contraction depends upon the movement of calcium, sodium and potassium through ion channels in the cell membrane and T-tubules . Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant of those. Metal cofactors are bound tightly to specific sites in proteins; although enzyme cofactors can be modified during catalysis, they always return to their original state by

8736-462: The existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups. The detoxification of

8848-476: The family of ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted. The detoxification of endogenous reactive metabolites such as peroxides and reactive aldehydes often cannot be achieved by the system described above. This

8960-414: The fatty acids are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids release more energy upon oxidation than carbohydrates. Steroids are also broken down by some bacteria in a process similar to beta oxidation, and this breakdown process involves the release of significant amounts of acetyl-CoA, propionyl-CoA, and pyruvate, which can all be used by

9072-484: The first stage, large organic molecules, such as proteins , polysaccharides or lipids , are digested into their smaller components outside cells. Next, these smaller molecules are taken up by cells and converted to smaller molecules, usually acetyl coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on acetyl-CoA is oxidized to water and carbon dioxide in the citric acid cycle and electron transport chain , releasing more energy while reducing

9184-405: The form of water-soluble messengers such as hormones and growth factors and are detected by specific receptors on the cell surface. These signals are then transmitted inside the cell by second messenger systems that often involved the phosphorylation of proteins. A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone insulin . Insulin

9296-598: The generation of a highly-reactive oxyferryl species, according to the following scheme: Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation , reduction , hydrolysis , cyclization , decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines , paracetamol , and steroids. If

9408-419: The investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams of the book Detoxication mechanisms in 1947. This modern biochemical research resulted in the identification of glutathione S -transferases in 1961, followed by the discovery of cytochrome P450s in 1962, and

9520-456: The laboratory using non-enzyme catalysts. This example of a biomimetic reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical trimebutine , desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of an N-methyl group leads to expulsion of

9632-454: The liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the gut , and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein , it becomes well-metabolized and is said to show

9744-529: The major route of breakdown is glycolysis , in which glucose is converted into pyruvate . This process generates the energy-conveying molecule NADH from NAD , and generates ATP from ADP for use in powering many processes within the cell. Pyruvate is an intermediate in several metabolic pathways, but the majority is converted to acetyl-CoA and fed into the citric acid cycle , which enables more ATP production by means of oxidative phosphorylation . This oxidation consumes molecular oxygen and releases water and

9856-506: The majority of the carbon and nitrogen; most of the oxygen and hydrogen is present as water. The abundant inorganic elements act as electrolytes . The most important ions are sodium , potassium , calcium , magnesium , chloride , phosphate and the organic ion bicarbonate . The maintenance of precise ion gradients across cell membranes maintains osmotic pressure and pH . Ions are also critical for nerve and muscle function, as action potentials in these tissues are produced by

9968-680: The mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be fixed by the Calvin–Benson cycle, a reversed citric acid cycle, or the carboxylation of acetyl-CoA. Prokaryotic chemoautotrophs also fix CO 2 through the Calvin–Benson cycle, but use energy from inorganic compounds to drive the reaction. In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch . The generation of glucose from compounds like pyruvate , lactate , glycerol , glycerate 3-phosphate and amino acids

10080-482: The metabolic pathway self-regulates to respond to changes in the levels of substrates or products; for example, a decrease in the amount of product can increase the flux through the pathway to compensate. This type of regulation often involves allosteric regulation of the activities of multiple enzymes in the pathway. Extrinsic control involves a cell in a multicellular organism changing its metabolism in response to signals from other cells. These signals are usually in

10192-483: The metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system , which acts to dispose of the reactive aldehyde methylglyoxal , and the various antioxidant systems that remove reactive oxygen species . Quantitatively, the smooth endoplasmic reticulum of the liver cell is the principal organ of drug metabolism, although every biological tissue has some ability to metabolize drugs. Factors responsible for

10304-428: The metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate. A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts

10416-512: The most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy ( starch , glycogen ) and structural components ( cellulose in plants, chitin in animals). The basic carbohydrate units are called monosaccharides and include galactose , fructose , and most importantly glucose . Monosaccharides can be linked together to form polysaccharides in almost limitless ways. The two nucleic acids, DNA and RNA , are polymers of nucleotides . Each nucleotide

10528-478: The most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system . These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates. The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and

10640-420: The nature of photosynthetic pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have two. In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing oxygen as a waste product. The electrons then flow to the cytochrome b6f complex , which uses their energy to pump protons across the thylakoid membrane in

10752-412: The pathway. Terpenes and isoprenoids are a large class of lipids that include the carotenoids and form the largest class of plant natural products . These compounds are made by the assembly and modification of isoprene units donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate . These precursors can be made in different ways. In animals and archaea,

10864-480: The potential or real toxicity of the compound is taken into account ( ADME-Tox or ADMET ). Parameters used to characterize toxicity include the median lethal dose ( LD 50 ) and therapeutic index . Computational chemists try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR . The route of administration critically influences ADME. Drug Disposition Drug metabolism

10976-674: The precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine , glutamine , and aspartic acid , as well as formate transferred from the coenzyme tetrahydrofolate . Pyrimidines , on the other hand, are synthesized from the base orotate , which is formed from glutamine and aspartate. All organisms are constantly exposed to compounds that they cannot use as foods and that would be harmful if they accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called xenobiotics . Xenobiotics such as synthetic drugs , natural poisons and antibiotics are detoxified by

11088-419: The reactive aldehyde methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species . The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells. In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of

11200-401: The reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system , which removes

11312-404: The realization of their central role in xenobiotic metabolism in 1963. Metabolism Metabolism ( / m ə ˈ t æ b ə l ɪ z ə m / , from Greek : μεταβολή metabolē , "change") is the set of life -sustaining chemical reactions in organisms . The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes;

11424-430: The removal of the amino group by a transaminase . The amino group is fed into the urea cycle , leaving a deaminated carbon skeleton in the form of a keto acid . Several of these keto acids are intermediates in the citric acid cycle, for example α- ketoglutarate formed by deamination of glutamate . The glucogenic amino acids can also be converted into glucose, through gluconeogenesis . In oxidative phosphorylation,

11536-627: The source of constructed molecules in their cells. Autotrophs such as plants can construct the complex organic molecules in their cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water. Heterotrophs , on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from light, whereas chemoautotrophs and chemoheterotrophs obtain energy from oxidation reactions. Photosynthesis

11648-747: The structure of drugs through degradation and biotransformation processes, thus altering the activity and toxicity of drugs. These processes can decrease the efficacy of drugs, as is the case of digoxin in the presence of Eggerthella lenta in the microbiota. Genetic variation ( polymorphism ) accounts for some of the variability in the effect of drugs. In general, drugs are metabolized more slowly in fetal , neonatal and elderly humans and animals than in adults . Inherited genetic variations in drug metabolising enzymes result in their different catalytic activity levels. For example, N-acetyltransferases (involved in Phase II reactions), individual variation creates

11760-426: The substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehyde could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation , acetylation , and sulfonation . In the early twentieth century, work moved on to

11872-425: The substrate can be acceptors, the polysaccharides produced can have straight or branched structures. The polysaccharides produced can have structural or metabolic functions themselves, or be transferred to lipids and proteins by the enzymes oligosaccharyltransferases . Fatty acids are made by fatty acid synthases that polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by

11984-826: The table below. Organic molecules are used as a source of hydrogen atoms or electrons by organotrophs , while lithotrophs use inorganic substrates. Whereas phototrophs convert sunlight to chemical energy , chemotrophs depend on redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules , hydrogen , hydrogen sulfide or ferrous ions to oxygen , nitrate or sulfate . In animals, these reactions involve complex organic molecules that are broken down to simpler molecules, such as carbon dioxide and water. Photosynthetic organisms, such as plants and cyanobacteria , use similar electron-transfer reactions to store energy absorbed from sunlight. The most common set of catabolic reactions in animals can be separated into three main stages. In

12096-407: The tissue through glycogenesis which was usually being used to maintained glucose level in blood. Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-Glc) to an acceptor hydroxyl group on the growing polysaccharide. As any of the hydroxyl groups on the ring of

12208-480: The transfer of heat and work . The second law of thermodynamics states that in any isolated system , the amount of entropy (disorder) cannot decrease. Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are open systems that exchange matter and energy with their surroundings. Living systems are not in equilibrium , but instead are dissipative systems that maintain their state of high complexity by causing

12320-637: The transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary (or intermediate) metabolism. Metabolic reactions may be categorized as catabolic —the breaking down of compounds (for example, of glucose to pyruvate by cellular respiration ); or anabolic —the building up ( synthesis ) of compounds (such as proteins, carbohydrates, lipids, and nucleic acids). Usually, catabolism releases energy, and anabolism consumes energy. The chemical reactions of metabolism are organized into metabolic pathways , in which one chemical

12432-485: The uptake of useful molecules is mediated through transport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid -soluble xenobiotics using membrane barriers. However,

12544-465: The waste product carbon dioxide. When oxygen is lacking, or when pyruvate is temporarily produced faster than it can be consumed by the citric acid cycle (as in intense muscular exertion), pyruvate is converted to lactate by the enzyme lactate dehydrogenase , a process that also oxidizes NADH back to NAD for re-use in further glycolysis, allowing energy production to continue. The lactate is later converted back to pyruvate for ATP production where energy

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