HOME

TheInfoList



OR:

In
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
, a metabolic pathway is a linked series of
chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
s occurring within a
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
. The
reactant In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
s, products, and intermediates of an enzymatic reaction are known as
metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
, which are modified by a sequence of chemical reactions
catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
d by
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s. In most cases of a metabolic pathway, the
product Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...
of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell. These enzymes often require dietary minerals, vitamins, and other cofactors to function. Different metabolic pathways function based on the position within a eukaryotic cell and the significance of the pathway in the given compartment of the cell. For instance, the, electron transport chain, and oxidative phosphorylation all take place in the mitochondrial membrane. In contrast, glycolysis,
pentose phosphate pathway The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-pho ...
, and fatty acid biosynthesis all occur in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
of a cell. There are two types of metabolic pathways that are characterized by their ability to either synthesize molecules with the utilization of energy ( anabolic pathway), or break down complex molecules and release energy in the process ( catabolic pathway). The two pathways complement each other in that the energy released from one is used up by the other. The degradative process of a catabolic pathway provides the energy required to conduct the biosynthesis of an anabolic pathway. In addition to the two distinct metabolic pathways is the amphibolic pathway, which can be either catabolic or anabolic based on the need for or the availability of energy. Pathways are required for the maintenance of
homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
within an
organism In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...
and the flux of metabolites through a pathway is regulated depending on the needs of the cell and the availability of the substrate. The end product of a pathway may be used immediately, initiate another metabolic pathway or be stored for later use. The
metabolism Metabolism (, from el, 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 c ...
of a cell consists of an elaborate network of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism).


Overview

Each metabolic pathway consists of a series of biochemical reactions that are connected by their intermediates: the products of one reaction are the substrates for subsequent reactions, and so on. Metabolic pathways are often considered to flow in one direction. Although all chemical reactions are technically reversible, conditions in the cell are often such that it is thermodynamically more favorable for flux to proceed in one direction of a reaction. For example, one pathway may be responsible for the synthesis of a particular amino acid, but the breakdown of that amino acid may occur via a separate and distinct pathway. One example of an exception to this "rule" is the metabolism of
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
. Glycolysis results in the breakdown of glucose, but several reactions in the glycolysis pathway are reversible and participate in the re-synthesis of glucose ( gluconeogenesis). * Glycolysis was the first metabolic pathway discovered: # As
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
enters a cell, it is immediately
phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
by ATP to
glucose 6-phosphate Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way ...
in the irreversible first step. # In times of excess
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...
or
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
energy sources, certain reactions in the glycolysis pathway may run in reverse to produce
glucose 6-phosphate Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way ...
, which is then used for storage as glycogen or starch. * Metabolic pathways are often
regulated Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...
by feedback inhibition. * Some metabolic pathways flow in a 'cycle' wherein each component of the cycle is a substrate for the subsequent reaction in the cycle, such as in the
Krebs Cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
(see below). * Anabolic and catabolic pathways in eukaryotes often occur independently of each other, separated either physically by compartmentalization within organelles or separated biochemically by the requirement of different enzymes and co-factors.


Major metabolic pathways


Catabolic pathway (catabolism)

A catabolic pathway is a series of reactions that bring about a net release of energy in the form of a high energy phosphate bond formed with the energy carriers adenosine diphosphate (ADP) and guanosine diphosphate (GDP) to produce adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively. The net reaction is, therefore, thermodynamically favorable, for it results in a lower free energy for the final products. A catabolic pathway is an exergonic system that produces chemical energy in the form of ATP, GTP, NADH, NADPH, FADH2, etc. from energy containing sources such as carbohydrates, fats, and proteins. The end products are often carbon dioxide, water, and ammonia. Coupled with an endergonic reaction of anabolism, the cell can synthesize new macromolecules using the original precursors of the anabolic pathway. An example of a coupled reaction is the phosphorylation of fructose-6-phosphate to form the intermediate fructose-1,6-bisphosphate by the enzyme phosphofructokinase accompanied by the hydrolysis of ATP in the pathway of glycolysis. The resulting chemical reaction within the metabolic pathway is highly thermodynamically favorable and, as a result, irreversible in the cell. Fructose-6-Phosphate + ATP -> Fructose-1,6-Bisphosphate + ADP


Cellular respiration

A core set of energy-producing catabolic pathways occur within all living organisms in some form. These pathways transfer the energy released by breakdown of nutrients into ATP and other small molecules used for energy (e.g. GTP, NADPH, FADH2). All cells can perform
anaerobic respiration Anaerobic respiration is respiration using electron acceptors other than molecular oxygen (O2). Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain. In aerobic organisms undergoing r ...
by glycolysis. Additionally, most organisms can perform more efficient aerobic respiration through the citric acid cycle and oxidative phosphorylation. Additionally
plant Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
s, algae and cyanobacteria are able to use sunlight to anabolically synthesize compounds from non-living matter by photosynthesis.


Anabolic pathway (anabolism)

In contrast to catabolic pathways,
anabolic pathways Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an Endergonic reaction, endergonic process. Anabolism is the building-up aspect of metabolism, whereas cataboli ...
require an energy input to construct macromolecules such as polypeptides, nucleic acids, proteins, polysaccharides, and lipids. The isolated reaction of anabolism is unfavorable in a cell due to a positive
Gibbs Free Energy In thermodynamics, the Gibbs free energy (or Gibbs energy; symbol G) is a thermodynamic potential that can be used to calculate the maximum amount of work that may be performed by a thermodynamically closed system at constant temperature and ...
(+Δ''G''). Thus, an input of chemical energy through a coupling with an exergonic reaction is necessary. The coupled reaction of the catabolic pathway affects the thermodynamics of the reaction by lowering the overall activation energy of an anabolic pathway and allowing the reaction to take place. Otherwise, an endergonic reaction is non-spontaneous. An anabolic pathway is a biosynthetic pathway, meaning that it combines smaller molecules to form larger and more complex ones. An example is the reversed pathway of glycolysis, otherwise known as gluconeogenesis, which occurs in the liver and sometimes in the kidney to maintain proper glucose concentration in the blood and supply the brain and muscle tissues with adequate amount of glucose. Although gluconeogenesis is similar to the reverse pathway of glycolysis, it contains four distinct enzymes(
pyruvate carboxylase Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme () of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA). Image:Pyruvic-acid-2D-sk ...
,
phosphoenolpyruvate carboxykinase Phosphoenolpyruvate carboxykinase (, PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide. It is found in two forms, cytosolic and mitoch ...
, fructose 1,6-bisphosphatase, glucose 6-phosphatase) from glycolysis that allow the pathway to occur spontaneously.


Amphibolic pathway

An amphibolic pathway is one that can be either catabolic or anabolic based on the availability of or the need for energy. The currency of energy in a biological cell is adenosine triphosphate (ATP), which stores its energy in the phosphoanhydride bonds. The energy is utilized to conduct biosynthesis, facilitate movement, and regulate active transport inside of the cell. Examples of amphibolic pathways are the citric acid cycle and the glyoxylate cycle. These sets of chemical reactions contain both energy producing and utilizing pathways. To the right is an illustration of the amphibolic properties of the TCA cycle. The glyoxylate shunt pathway is an alternative to the tricarboxylic acid (TCA) cycle, for it redirects the pathway of TCA to prevent full oxidation of carbon compounds, and to preserve high energy carbon sources as future energy sources. This pathway occurs only in plants and bacteria and transpires in the absence of glucose molecules.


Regulation

The flux of the entire pathway is regulated by the rate-determining steps. These are the slowest steps in a network of reactions. The rate-limiting step occurs near the beginning of the pathway and is regulated by feedback inhibition, which ultimately controls the overall rate of the pathway. The metabolic pathway in the cell is regulated by covalent or non-covalent modifications. A covalent modification involves an addition or removal of a chemical bond, whereas a non-covalent modification (also known as allosteric regulation) is the binding of the regulator to the enzyme via hydrogen bonds, electrostatic interactions, and
Van Der Waals forces In molecular physics, the van der Waals force is a distance-dependent interaction between atoms or molecules. Unlike ionic or covalent bonds, these attractions do not result from a chemical electronic bond; they are comparatively weak and th ...
. The rate of turnover in a metabolic pathway, also known as the metabolic flux, is regulated based on the stoichiometric reaction model, the utilization rate of metabolites, and the translocation pace of molecules across the
lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
. The regulation methods are based on experiments involving 13C-labeling, which is then analyzed by Nuclear Magnetic Resonance (NMR) or gas chromatography-mass spectrometry (GC-MS)-derived mass compositions. The aforementioned techniques synthesize a statistical interpretation of mass distribution in
proteinogenic amino acid Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation. The word "proteinogenic" means "protein creating". Throughout known life, there are 22 genetically encoded (proteinogenic) amino aci ...
s to the catalytic activities of enzymes in a cell.


Clinical applications in targeting metabolic pathways


Targeting Oxidative Phosphorylation

Metabolic pathways can be targeted for clinically therapeutic uses. Within the mitochondrial metabolic network, for instance, there are various pathways that can be targeted by compounds to prevent cancer cell proliferation. One such pathway is oxidative phosphorylation (OXPHOS) within the electron transport chain (ETC). Various inhibitors can downregulate the electrochemical reactions that take place at Complex I, II, III, and IV, thereby preventing the formation of an electrochemical gradient and downregulating the movement of electrons through the ETC. The substrate-level phosphorylation that occurs at ATP synthase can also be directly inhibited, preventing the formation of ATP that is necessary to supply energy for cancer cell proliferation. Some of these inhibitors, such as
lonidamine Lonidamine is a derivative of indazole-3-carboxylic acid, which for a long time, has been known to inhibit aerobic glycolysis in cancer cells. It seems to enhance aerobic glycolysis in normal cells, but suppress glycolysis in cancer cells. This i ...
and atovaquone, which inhibit Complex II and Complex III, respectively, are currently undergoing clinical trials for FDA-approval. Other non-FDA-approved inhibitors have still shown experimental success in vitro.


Targeting Heme

Heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
, an important prosthetic group present in Complexes I, II, and IV can also be targeted, since heme biosynthesis and uptake have been correlated with increased cancer progression. Various molecules can inhibit heme via different mechanisms. For instance,
succinylacetone Succinylacetone is a chemical compound that is formed by the oxidation of glycine and is a precursor of methylglyoxal Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a ...
has been shown to decrease heme concentrations by inhibiting δ-aminolevulinic acid in murine erythroleukemia cells. The primary structure of heme-sequestering peptides, such as HSP1 and HSP2, can be modified to downregulate heme concentrations and reduce proliferation of non-small lung cancer cells.


Targeting the Tricarboxylic acid cycle and Glutaminolysis

The tricarboxylic acid cycle (TCA) and glutaminolysis can also be targeted for cancer treatment, since they are essential for the survival and proliferation of cancer cells.
Ivosidenib Ivosidenib, sold under the brand name Tibsovo, is an anti-cancer medication for the treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. It is a small molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), which is mutated in se ...
and Enasidenib, two FDA-approved cancer treatments, can arrest the TCA cycle of cancer cells by inhibiting isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2), respectively. Ivosidenib is specific to acute myeloma leukemia (AML) and cholangiocarcinoma, whereas Enasidenib is specific to just acute myeloma leukemia (AML). In a clinical trial consisting of 185 adult patients with cholangiocarcinoma and an IDH-1 mutation, there was a statistically significant improvement (p<0.0001; HR: 0.37) in patients randomized to Ivosidenib. Still, some of the adverse side effects in these patients included fatigue, nausea, diarrhea, decreased appetite, ascites, and anemia. In a clinical trial consisting of 199 adult patients with AML and an IDH2 mutation, 23% of patients experienced complete response (CR) or complete response with partial hematologic recovery (CRh) lasting a median of 8.2 months while on Enasidenib. Of the 157 patients who required transfusion at the beginning of the trial, 34% no longer required transfusions during the 56-day time period on Enasidenib. Of the 42% of patients who did not require transfusions at the beginning of the trial, 76% still did not require a transfusion by the end of the trial. Side effects of Enasidenib included nausea, diarrhea, elevated bilirubin and most notably, differentiation syndrome. Glutaminase (GLS), the enzyme responsible for converting glutamine to glutamate via hydrolytic deamidation during the first reaction of glutaminolysis, can also be targeted. In recent years, many small molecules, such as azaserine, acivicin, and CB-839 have been shown to inhibit glutaminase, thus reducing cancer cell viability and inducing apoptosis in cancer cells. Due to its effective antitumor ability in several cancer types such as ovarian, breast and lung cancers, CB-839 is the only GLS inhibitor currently undergoing clinical studies for FDA-approval.


Genetic engineering of metabolic pathways

Many metabolic pathways are of commercial interest. For instance, the production of many
antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
or other drugs requires complex pathways. The pathways to produce such compounds can be transplanted into microbes or other more suitable organism for production purposes. For example, the world's supply of the anti-cancer drug
vinblastine Vinblastine (VBL), sold under the brand name Velban among others, is a chemotherapy medication, typically used with other medications, to treat a number of types of cancer. This includes Hodgkin's lymphoma, non-small cell lung cancer, bladder ca ...
is produced by relatively ineffient extraction and purification of the precursors vindoline and catharanthine from the plant ''
Catharanthus roseus ''Catharanthus roseus'', commonly known as bright eyes, Cape periwinkle, graveyard plant, Madagascar periwinkle, old maid, pink periwinkle, rose periwinkle, is a species of flowering plant in the family Apocynaceae. It is native and endemic to M ...
'', which are then chemically converted into vinblastine. The biosynthetic pathway to produce vinblastine, including 30 enzymatic steps, has been transferred into yeast cells which is a convenient system to grow in large amounts. With these genetic modifications yeast can use its own metabolites
geranyl pyrophosphate Geranyl pyrophosphate (GPP), also known as geranyl diphosphate (GDP), is the pyrophosphate ester of the terpenoid geraniol. Its salts are colorless. It is a precursor to many natural products. Occurrence GPP is an intermediate in the isopreno ...
and tryptophan to produce the precursors of catharanthine and vindoline. This process required 56 genetic edits, including expression of 34 heterologous genes from plants in yeast cells.


See also

* KaPPA-View4 (2010) *
Metabolism Metabolism (, from el, 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 c ...
*
Metabolic control analysis Metabolic control analysis (MCA) is a mathematical framework for describing metabolic, signaling, and genetic pathways. MCA quantifies how variables,elastsuch as fluxes and species concentrations, depend on network parameters. In particular, it is a ...
*
Metabolic network A metabolic network is the complete set of metabolic and physical processes that determine the physiological and biochemical properties of a cell. As such, these networks comprise the chemical reactions of metabolism, the metabolic pathways, as w ...
* Metabolic network modelling * Metabolic engineering * Shq1


References


External links


Full map of metabolic pathways



Overview Map from BRENDA

BioCyc: Metabolic network models for thousands of sequenced organisms

KEGG: Kyoto Encyclopedia of Genes and Genomes

Reactome, a database of reactions, pathways and biological processes

MetaCyc: A database of experimentally elucidated metabolic pathways (2,200+ pathways from more than 2,500 organisms).

MetaboMAPS: A platform for pathway sharing and data visualization on metabolic pathways

The Pathway Localization database (PathLocdb)

DAVID: Visualize genes on pathway maps

Wikipathways: pathways for the people

ConsensusPathDB

''metpath'': Integrated interactive metabolic chart
{{DEFAULTSORT:Metabolic Pathway *