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, c ...
, 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. A ...
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
Cofactor may also refer to:
* Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed
* A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
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
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
, and
oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
all take place in the mitochondrial membrane.
In contrast,
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
,
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
Fatty is a derogatory term for someone who is obese. It may refer also to:
People
* Mai Fatty, Gambian politician
* Roscoe Arbuckle (1887–1933), American actor and comedian
* Fatty Briody (1858–1903), American Major League Baseball player ...
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
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...
).
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
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. ...
of an anabolic pathway.
In addition to the two distinct metabolic pathways is the
amphibolic
The term amphibolic ( grc, ἀμφίβολος, translit=amphibolos, lit=ambiguous, struck on both sides) is used to describe a biochemical pathway that involves both catabolism and anabolism. Catabolism is a degradative phase of metabolism in w ...
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 English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
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
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ph ...
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 cell ...
of a cell consists of an elaborate
network
Network, networking and networked may refer to:
Science and technology
* Network theory, the study of graphs as a representation of relations between discrete objects
* Network science, an academic field that studies complex networks
Mathematics
...
of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism).
Overview
![Net reactions for glycolysis of glucose, oxidative decarboxylation of pyruvate, and Krebs cycle](https://upload.wikimedia.org/wikipedia/commons/b/b5/Net_reactions_for_glycolysis_of_glucose%2C_oxidative_decarboxylation_of_pyruvate%2C_and_Krebs_cycle..png)
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
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ph ...
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, using ...
.
Glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
results in the breakdown of glucose, but several reactions in the glycolysis pathway are reversible and participate in the re-synthesis of glucose (
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
).
*
Glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
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, using ...
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, whi ...
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 wa ...
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 include ...
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, respo ...
energy sources, certain reactions in the
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
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 wa ...
, which is then used for storage as
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
or
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
.
* 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
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
.
* 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
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
and
catabolic
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
pathways in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
often occur independently of each other, separated either physically by compartmentalization within
organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
or separated biochemically by the requirement of different enzymes and co-factors.
Major metabolic pathways
Catabolic pathway (catabolism)
A
catabolic pathway
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...
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
Fructose 1,6-bisphosphate, also known as Harden-Young ester, is fructose sugar phosphorylated on carbons 1 and 6 (i.e., is a fructosephosphate). The β-D-form of this compound is common in cells. Upon entering the cell, most glucose and fructos ...
by the enzyme
phosphofructokinase
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
accompanied by the hydrolysis of ATP in the pathway of
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
. 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
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
pathways occur within all living organisms in some form. These pathways transfer the energy released by breakdown of
nutrient
A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s into
ATP and other small molecules used for energy (e.g.
GTP,
NADPH
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NAD ...
,
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 re ...
by
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
. Additionally, most organisms can perform more efficient
aerobic respiration
Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
through the
citric acid 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 proteins ...
and
oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
. 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 exclud ...
s,
algae
Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic eukaryotic organisms. It is a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from unicellular mic ...
and
cyanobacteria
Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, blu ...
are able to use sunlight to
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
ally synthesize compounds from non-living matter by
photosynthesis
Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
.
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 pr ...
(+Δ''G''). Thus, an input of chemical energy through a coupling with an
exergonic reaction
In thermochemistry, chemical thermodynamics, an exergonic reaction is a chemical reaction where the change in the thermodynamic free energy, free energy is negative (there is a net release of free energy). This indicates a spontaneous reaction if ...
is necessary.
The coupled reaction of the catabolic pathway affects the thermodynamics of the reaction by lowering the overall
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
of an anabolic pathway and allowing the reaction to take place.
Otherwise, an
endergonic reaction
In chemical thermodynamics, an endergonic reaction (; also called a heat absorbing nonspontaneous reaction or an unfavorable reaction) is a chemical reaction in which the standard change in free energy is positive, and an additional driving fo ...
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
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
, 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
The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are b ...
,
glucose 6-phosphatase
The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:
: D-glucose 6-phos ...
) from glycolysis that allow the pathway to occur spontaneously.
Amphibolic pathway
![Amphibolic Properties of the Citric Acid Cycle](https://upload.wikimedia.org/wikipedia/commons/c/cd/Amphibolic_Properties_of_the_Citric_Acid_Cycle.gif)
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 bond
In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
s, 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 bond, ionic or covalent bonds, these attractions do not result from a Chemical bond, chemical electronic bond; they are c ...
.
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
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
(OXPHOS) within the
electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
(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 is ...
and
atovaquone,
which inhibit Complex II and Complex III, respectively, are currently undergoing clinical trials for
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
-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 "consisti ...
, 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
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 proteins ...
(TCA) and
glutaminolysis Glutaminolysis (''glutamine'' + '' -lysis'') is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.
The glutaminolytic pathway
Glutaminolysis partia ...
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
Glutaminase (, ''glutaminase I'', ''L-glutaminase'', ''glutamine aminohydrolase'') is an amidohydrolase enzyme that generates glutamate from glutamine. Glutaminase has tissue-specific isoenzymes. Glutaminase has an important role in glial cells ...
(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
Vindoline is a chemical precursor to vinblastine.
Vindoline is formed through biosynthesis from Tabersonine
Tabersonine is a terpene indole alkaloid found in the medicinal plant ''Catharanthus roseus'' and also in the genus Voacanga (both taxa b ...
and
catharanthine
Catharanthine is a terpene indole alkaloid produced by the medicinal plant ''Catharanthus roseus'' and '' Tabernaemontana divaricata''. Catharanthine is derived from strictosidine, but the exact mechanism by which this happens is currently unknow ...
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 isoprenoid ...
and
tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α- carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
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
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KaPPA-View4
KaPPA-View4 is a metabolic pathway database containing data about metabolic regulation from 'omics' data.
See also
* Metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The re ...
(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 cell ...
*
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 network modelling, also known as metabolic network reconstruction or metabolic pathway analysis, allows for an in-depth insight into the molecular mechanisms of a particular organism. In particular, these models correlate the genome wi ...
*
Metabolic engineering
Metabolic engineering is the practice of optimizing genetic and regulatory processes within cells to increase the cell's production of a certain substance. These processes are chemical networks that use a series of biochemical reactions and enzy ...
*
Shq1
Shq1p is a protein involved in the rRNA processing pathway. It was discovered by Pok Yang in the Chanfreau laboratory at UCLA. Depletion of Shq1p has led to decreased level of various H/ACA box snoRNAs (H/ACA box snoRNAs are responsible for pse ...
References
External links
Full map of metabolic pathwaysOverview Map from BRENDABioCyc: Metabolic network models for thousands of sequenced organismsKEGG: Kyoto Encyclopedia of Genes and GenomesReactome, a database of reactions, pathways and biological processesMetaCyc: 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 pathwaysThe Pathway Localization database (PathLocdb)DAVID: Visualize genes on pathway mapsWikipathways: pathways for the peopleConsensusPathDB''metpath'': Integrated interactive metabolic chart
{{DEFAULTSORT:Metabolic Pathway
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