- 1 Distinctions Among different forms of Cellular Mechanisms
- 2 Mechanism in General
- 3 Mechanism of Action
- 4 Mode of Action
- 5 Biological Pathways
- 6 Metabolic pathway
- 7 Genetic Pathway
- 8 Signal transduction pathway
- 9 Biochemical cascade
- 10 Adverse outcome pathway
- 11 “Laws” and Principles
- 12 Reference and Precision Notes
To encourage informed consent, compliance and efficiency, it’s usually better to help the client to have a better grasp (understanding) on the mechanisms of action, biochemical pathways, pharmacodynamic processes and, among others, signaling cascades that promote diseases, their resolution and homeostasis (balance). Once the client understands what’s going on, he or she will usually be better motivated to put in place an efficient remedial plan of action.
Below, a few of these mechanisms. They can be examined on the homepage, by scrolling under the word “mechanisms” in the menu section where the links are alive.
Distinctions Among different forms of Cellular Mechanisms
In system theory, we have structure, function and mechanisms. Structures are physical energy end points. Functions are the processes by which structures operate. But mechanisms of action, which evolve within the very temporal-space structure of Life, are designed to maximize the self replication engine of Life.
These mechanisms are the organizing processes of Life, evolution and death, not just for humans and mammals, but for all species from the fundamental trio of Life, archaea, bacteria, (or prokaryotes, unicellular organisms) and multicellular eukaryote (1) of which the old Kingdom of mushrooms (fungi) are part. (2) These mechanisms also govern the entire phylogenetic Tree of Life (3) as well as the metabolism of cellular organisms (production of energy, sustainenance molecules and nitrogenous waste removal), their primary and secondary metabolies and health restoration when the body is out of balance and burden with disease. It’s useful to understand these mechanisms, if only because bacteria and viruses can kill or benefit us, for example, some microbiome bacterial waste, like hydrogen and methane is food for other bacteria which help their host humans to benefit from a smooth brain-gut (via vegas nerve) axis and many other biochemical pathways.
Mechanism in General
In the science of biology, which is big part of medicine, the general concept of mechanism means a system of casually interacting parts and processes that produce one or more effects. Scientists explain phenomena by describing mechanisms that could produce the phenomena. For example, natural selection based on prey-predator and host-parasite competition is a mechanism of biological evolution and ecology. Other mechanisms of evolution include genetic drift, mutation, and gene flow, to which the epigenetics experts have started to add “memes”, what Lamark called an inherited human behavior..
Mechanism of Action
The mechanism of action of aspirin for example involves inhibition of the enzyme cyclo-oxygenase. thanks to which pain and inflammation are reduced. This mechanism of action is specific to aspirin, and is not constant for all nonsteroidal anti-inflammatory drugs (NSAIDs). (4)
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. (5) A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. (6)
Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there. Drugs that do not bind to receptors produce their corresponding therapeutic effect by simply interacting with chemical or physical properties in the body. Common examples of drugs that work in this way are antacids and laxatives. (7)
Mode of Action
In comparison, a mode of action (MoA) describes functional or anatomical changes, at the cellular level, resulting from the exposure of a living organism to a substance. (8) This differs from a mechanism of action, as it is a more specific term that focuses on the interaction between the drug itself and an enzyme or receptor and its particular form of interaction, whether through inhibition, activation, agonism, or antagonism. Furthermore, the term mechanism of action is the main term that is primarily used in pharmacology, whereas mode of action will more often appear in the field of microbiology or certain aspects of biology.
A mode of action is important in classifying chemicals as it represents an intermediate level of complexity in between molecular mechanisms and physiological outcomes, especially when the exact molecular target has not yet been elucidated or is subject to debate. A mechanism of action of a chemical could be “binding to DNA” while its broader mode of action would be “transcriptional regulation”. (9) However, there is no clear consensus and the term mode of action is also often used, especially in the study of pesticides, to describe molecular mechanisms such as action on specific nuclear receptors or enzymes. (10)
A biological pathways are a series of interactions among molecules in a cell that leads to a certain product or a change in a cell. Such a pathway can trigger the assembly of new molecules, such as a fat or protein. Pathways can also turn genes on and off, or spur a cell to move. Some of the most common biological pathways are involved in metabolism, the regulation of gene expression and the transmission of signals. Pathways play key role in advanced studies of genomics. Most common types of biological pathways: •Metabolic pathway •Genetic pathway•Signal transduction pathway (11)
As the viewer can visually see with a mouse click in this link, these pathways can be quite complex
In biochemistry, a metabolic pathway, sometimes called biochemical pathway, is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. (12) In a metabolic pathway, the product of one enzyme acts as the substrate for the next.
These enzymes often require dietary minerals, vitamins, and other cofactors to function, thus holistic nutritional science is key for the proper functioning of cells.
Different metabolic pathways function based on the position within an eukaryotic cell and the significance of the pathway in the given compartment of the cell. (13) For instance, three of the most important metabolic pathways, the citric acid cycle, electron transport chain, and oxidative phosphorylation all take place in the mitochondrial membrane. In contrast, glycolysis, pentose phosphate pathway, and fatty acid biosynthesis all occur in the cytosol of a cell. (14). A cancer cell for example thrives thanks to glyclysis were as normal cells thrive thanks to oxidative phophorylation pathway.
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 of complex molecules by releasing energy in the process (catabolic pathway). (15) 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 a 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. (16) .
Pathways are required for the maintenance of homeostasis within an organism 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 of a cell consists of an elaborate network of interconnected pathways that enable the synthesis and breakdown of molecules (anabolism and catabolism)
Main article: 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, FADH). All cells can perform anaerobic respiration by glycolysis. Additionally, most organisms can perform more efficient aerobic respiration through the citric acid cycle and oxidative phosphorylation. Additionally plants, algae and cyanobacteria are able to use sunlight to anabolically synthesize compounds from non-living matter by photosynthesis.
A gene (or genetic) regulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression levels of mRNA and proteins. These play a central role in morphogenesis, the creation of body structures, which in turn is central to evolutionary developmental biology (evo-devo).
The regulator can be DNA, RNA, protein and complexes of these. The interaction can be direct or indirect (through transcribed RNA or translated protein). In general, each mRNA molecule goes on to make a specific protein (or set of proteins). In some cases this protein will be structural, and will accumulate at the cell membrane or within the cell to give it particular structural properties. In other cases the protein will be an enzyme, i.e., a micro-machine that catalyses a certain reaction, such as the breakdown of a food source or toxin. Some proteins though serve only to activate other genes, and these are the transcription factors that are the main players in regulatory networks or cascades. By binding to the promoter region at the start of other genes they turn them on, initiating the production of another protein, and so on. Some transcription factors are inhibitory.
In single-celled organisms, regulatory networks respond to the external environment, optimising the cell at a given time for survival in this environment. Thus a yeast cell, finding itself in a sugar solution, will turn on genes to make enzymes that process the sugar to alcohol. This process, which we associate with wine-making, is how the yeast cell makes its living, gaining energy to multiply, which under normal circumstances would enhance its survival prospects.
In multicellular animals the same principle has been put in the service of gene cascades that control body-shape. Each time a cell divides, two cells result which, although they contain the same genome in full, can differ in which genes are turned on and making proteins. Sometimes a ‘self-sustaining feedback loop’ ensures that a cell maintains its identity and passes it on. Less understood is the mechanism of epigenetics by which chromatin modification may provide cellular memory by blocking or allowing transcription.
A major feature of multicellular animals is the use of morphogen gradients, which in effect provide a positioning system that tells a cell where in the body it is, and hence what sort of cell to become. A gene that is turned on in one cell may make a product that leaves the cell and diffuses through adjacent cells, entering them and turning on genes only when it is present above a certain threshold level. These cells are thus induced into a new fate, and may even generate other morphogens that signal back to the original cell. Over longer distances morphogens may use the active process of signal transduction. Such signalling controls embryogenesis, the building of a body plan from scratch through a series of sequential steps. They also control and maintain adult bodies through feedback processes, and the loss of such feedback because of a mutation can be responsible for the cell proliferation that is seen in cancer. In parallel with this process of building structure, the gene cascade turns on genes that make structural proteins that give each cell the physical properties it needs.
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^ DH Latchman. “Inhibitory transcription factors”. Biochem Cell Bio.
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^ “Transcriptional Regulatory Networks in Saccharomyces cerevisiae“. Young Lab.
Signal transduction pathway
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalysed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a signaling cascade, which is a chain of biochemical events along a signaling pathway. When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events. At the molecular level, such responses include changes in the transcription or translation of genes, and post-translational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes. In multicellular organisms, signal transduction pathways have evolved to regulate cell communication in a wide variety of ways.
Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. Ligands are termed first messengers, while receptors are the signal transducers, which then activate primary effectors. Such effectors are often linked to second messengers, which can activate secondary effectors, and so on. Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signaling molecule can generate a response involving hundreds to millions of molecules. As with other signals, the transduction of biological signals is characterised by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological. With the advent of computational biology, the analysis of signaling pathways and networks has become an essential tool to understand cellular functions and disease, including signaling rewiring mechanisms underlying responses to acquired drug resistance.
Main article: Stimulus (physiology)
The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition. Traditionally, signals that reach the central nervous system are classified as senses. These are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.
Main article: Ligand (biochemistry)
The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation. Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors. These include growth factors, cytokines and neurotransmitters.
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^ Papin, Jason A.; Hunter, Tony; Palsson, Bernhard O.; Subramaniam, Shankar (14 January 2005). “Reconstruction of cellular signalling networks and analysis of their properties”. Nature Reviews Molecular Cell Biology. 6 (2): 99–111. doi:10.1038/nrm1570. PMID 15654321.
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^ Kolch, Walter; Halasz, Melinda; Granovskaya, Marina; Kholodenko, Boris N. (20 August 2015). “The dynamic control of signal transduction networks in cancer cells”. Nature Reviews Cancer. 15 (9): 515–527. doi:10.1038/nrc3983. PMID 26289315.
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^ Bago R, Sommer E, Castel P, Crafter C, Bailey FP, Shpiro N, Baselga J, Cross D, Eyers PA, Alessi DR (2016) The hVps34-SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth. EMBO Journal 35:1902-22
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^ Lawrence, Peter A.; Levine, Michael (April 2006). “Mosaic and regulative development: two faces of one coin”. Current Biology. 16 (7): R236–R239. doi:10.1016/j.cub.2006.03.016. PMID 16581495.
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions which are initiated by a stimulus (first messenger) acting on a receptor that is transduced to the cell interior through second messengers (which amplify the initial signal) and ultimately to effector molecules, resulting in a cell response to the initial stimulus. At each step of the signaling cascade, various controlling factors are involved to regulate cellular actions, responding effectively to cues about their changing internal and external environments.
Cells require a full and functional cellular machinery to live. When they belong to complex multicellular organisms, they need to communicate among themselves and work for symbiosis in order to give life to the organism. These communications between cells triggers intracellular signaling cascades, termed signal transduction pathways, that regulate specific cellular functions. Each signal transduction occurs with a primary extracellular messenger that binds to a transmembrane or nuclear receptor, initiating intracellular signals. The complex formed produces or releases second messengers that integrate and adapt the signal, amplifying it, by activating molecular targets, which in turn trigger effectors that will lead to the desired cellular response.
Transductors and effectors
Signal transduction is realized by activation of specific receptors and consequent production/delivery of second messengers, as Ca2+ or cAMP. These molecules operate as signal transducers, triggering intracellular cascades and in turn amplifying the initial signal. Two main signal transduction mechanisms have been identified, via nuclear receptors, or via transmembrane receptors. In the first one, first messenger cross through the cell membrane, binding and activating intracellular receptors localized at nucleus or cytosol, which then act as transcriptional factors regulating directly gene expression. This is possible due to the lipophilic nature of those ligands, mainly hormones. In the signal transduction via transmembrane receptors, first messenger bind to the extracellular domain of transmembrane receptor activating it. This receptors may have intrinsic catalytic activity or may be coupled to effector enzymes, or may also be associated to ionic channels. Therefore, there are four main transmembrane receptor types: G protein coupled receptors (GPCRs), tyrosine kinase receptors (RTKs), serine/threonine kinase receptors (RSTKs), and ligand-gated ion channels (LGICs). Second messengers can be classified into three classes:
1Hydrophilic/cytosolic – are soluble in water and are localized at the cytosol, including cAMP, cGMP, IP3, Ca2+, cADPR and S1P. Their main targets are protein kinases as PKA and PKG, being then involved in phosphorylation mediated responses.
2Hydrophobic/membrane-associated – are insoluble in water and membrane-associated, being localized at intermembrane spaces, where they can bind to membrane-associated effector proteins. Examples: PIP3, DAG, phosphatidic acid, arachidonic acid and ceramide. They are involved in regulation of kinases and phosphatases, G protein associated factors and transcriptional factors.
3Gaseous – can be widespread through cell membrane and cytosol, including nitric oxide and carbon monoxide. Both of them can activate cGMP and, besides of being capable of mediating independent activities, they also can operate in a coordinated mode.
The cellular response in signal transduction cascades involves alteration of the expression of effector genes or activation/inhibition of targeted proteins. Regulation of protein activity mainly involves phosphorylation/dephosphorylation events,
Examples of biochemical cascades
In biochemistry, several important enzymatic cascades and signal transduction cascades participate in metabolic pathways or signaling networks, in which enzymes are usually involved to catalyze the reactions. For example, the tissue factor pathway in the coagulation cascade of secondary hemostasis is the primary pathway leading to fibrin formation, and thus, the initiation of blood coagulation. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factors are activated to become active components that then catalyze the next reaction in the ca
Alzheimer’s disease (AD)
Synaptic degeneration and death of nerve cells are defining features of Alzheimer’s disease (AD), the most prevalent age-related neurodegenerative disorders. In AD, neurons in the hippocampus and basal forebrain (brain regions that subserve learning and memory functions) are selectively vulnerable. Studies of postmortem brain tissue from AD people have provided evidence for increased levels of oxidative stress, mitochondrial dysfunction and impaired glucose uptake in vulnerable neuronal populations. Studies of animal and cell culture models of AD suggest that increased levels of oxidative stress (membrane lipid peroxidation, in particular) may disrupt neuronal energy metabolism and ion homeostasis, by impairing the function of membrane ion-motive ATPases, glucose and glutamate transporters. Such oxidative and metabolic compromise may thereby render neurons vulnerable to excitotoxicity and apoptosis. Recent studies suggest that AD can manifest systemic alterations in energy metabolism (e.g., increased insulin resistance and dysregulation of glucose metabolism). Emerging evidence that dietary restriction can forestall the development of AD is consistent with a major “metabolic” component to these disorders, and provides optimism that these devastating brain disorders of aging may be largely preventable.
^ Mattson, M. P.; Pedersen, W. A.; Duan, W.; Culmsee, C.; Camandola, S. (1999). “Cellular and Molecular Mechanisms Underlying Perturbed Energy Metabolism and Neuronal Degeneration in Alzheimer’s and Parkinson’s Diseases”. Annals of the New York Academy of Sciences. 893: 154–175. doi:10.1111/j.1749-6632.1999.tb07824.x.
Adverse outcome pathway
The AOP links in a linear way one or more series of causally connected key events (KE) between two points, a molecular initiating event (MIE) and an adverse outcome (AO) that occur at a level of biological organization relevant to risk assessment.
The linkage between the events is described by key event relationships (KER) that describe the causal relationships between the key events.
AOPs are important for expanding the use of mechanistic toxicological data for risk assessment and regulatory applications.
^ Academies, Committee on Toxicity Testing and Assessment of Environmental Agents, Board on Environmental Studies and Toxitology […], National Research Council of the National (2007). Toxicity testing in the 21st century : a vision and a strategy. Washington: The National Academic Press. ISBN 978-0-309-15173-3.
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a b c Ankley, Gerald T.; Bennett, Richard S.; Erickson, Russell J.; Hoff, Dale J.; Hornung, Michael W.; Johnson, Rodney D.; Mount, David R.; Nichols, John W.; Russom, Christine L.; Schmieder, Patricia K.; Serrrano, Jose A.; Tietge, Joseph E.; Villeneuve, Daniel L. (2010). “Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment”. Environmental Toxicology and Chemistry. 29 (3): 730–741. doi:10.1002/etc.34. PMID 20821501.
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a b “Adverse Outcome Pathways, Molecular Screening and Toxicogenomics”. OECD.
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^ Kramer, Vincent J.; Etterson, Matthew A.; Hecker, Markus; Murphy, Cheryl A.; Roesijadi, Guritno; Spade, Daniel J.; Spromberg, Julann A.; Wang, Magnus; Ankley, Gerald T. (2011). “Adverse outcome pathways and ecological risk assessment: Bridging to population-level effects”. Environmental Toxicology and Chemistry. 30 (1): 64–76. doi:10.1002/etc.375. PMID 20963853.
“Laws” and Principles
Contrary to societal laws ( ) physical laws which also govern biophysics, which is a huge part of human physiology. For example, Archimedes principle, relating buoyancy to the weight of displaced water, is an early example of a law in science. Another early one developed by Malthus is the population principle, now called the Malthusian principle. Freud also wrote on principles, especially the reality principle necessary to keep the id and pleasure principle in check. Biologists use the principle of priority and principle of Binominal nomenclature for precision in naming species. There are many principles observed in physics, notably in cosmology which observes the mediocrity principle, the anthropic principle, the principle of relativity and the cosmological principle, entropy, neguentropy and so on. Other well-known principles include the uncertainty principle in quantum mechanics and the pigeonhole principle and superposition principle in mathematics
It represents a set of values that inspire the written norms that organize the life of a society submitting to the powers of an authority, generally the State. The law establishes a legal obligation, in a coercive way; it therefore acts as principle conditioning of the action that limits the liberty of the individuals. See, for examples, the territorial principle, homestead principle, and precautionary principle.Reference and Precision Sources
Not to be confused with hemostasis.
Reference and Precision Notes
(1). The three-domain system is a biological classification introduced by Carl Woese et al. in 1977 (See first reference below), that divides cellular life forms into archaea, bacteria, (or prokaryotes, unicellular organism) and eukaryote domains. Woese argued that, on the basis of differences in 16S rRNA genes, these two groups and the eukaryotes each arose separately from a common ancestor with poorly developed genetic machinery, (called a progenote). To reflect these primary lines of descent, he treated each as a domain, divided into several different kingdoms. Woese initially used the term “kingdom” to refer to the three primary phylogenic groupings, and this nomenclature was widely used until the term “domain” was adopted in 1990. (See second reference) Woese C, Fox G (1977). “Phylogenetic structure of the bacteria domain: the primary kingdoms”. Proc Natl Acad Sci USA. 74 (11): 5088–90. And Woese C, Kandler O, Wheelis M (1990). “Towards a natural system of organisms: proposal for the domains Archaea, Bacteria, and Eucarya”. Proc Natl Acad Sci USA. 87 (12): 4576–9.
(2). The domain Eukarya: animals, plants, algae, protozoans, and fungi (yeasts, molds, mushrooms). Since viruses are acellular- they contain no cellular organelles, cannot grow and divide, and carry out no independent metabolism – they are considered neither prokaryotic nor eukaryotic. (faculty.ccbcmd.edu/courses/bio141/lecguide/unit1/proeu/proeu.html)
(3) A phylogeny is a proposal of how organisms are related by their evolutionary history. It is based on the evidence that all living things are related by common descent. The evidence for phylogeny comes from palaeontology, comparative anatomy, and DNA sequence analysis. The main product of phylogenetics is a phylogenetic tree or tree of life. This is a diagram showing a pattern of ancestor/descendent relationships. Information may be related to geological periods or estimated dates
(4). Sharma, S.; Sharma, S. C. (1997). “An update on eicosanoids and inhibitors of cyclooxygenase enzyme systems”. Indian Journal of Experimental Biology. 35 (10): 1025–1031
(5). Spratto, G.R.; Woods, A.L. (2010). Delmar Nurse’s Drug Handbook. Cengage Learning. ISBN 978-1-4390-5616-5.
(6) Grant, R.L.; Combs, A.B.; Acosta, D. (2010) “Experimental Models for the Investigation of Toxicological Mechanisms”. In McQueen, C.A. Comprehensive Toxicology (2nd ed.). Oxford: Elsevier. p. 204. ISBN
(7). Op Cit,Spratto.
(8). “Mechanisms and mode of dioxin action” (PDF). U.S. Environmental Protection Agency
(9). Cushnie, T.P.; O’Driscoll, N.H.; Lamb, A.J. (2016). “Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action”. Cellular and Molecular Life Sciences. 73 (23): 4471–4492. doi:10.1007/s00018-016-2302-2. PMID 27392605.
(13). Nicholson, Donald E. (March 1971). An Introduction to Metabolic Pathways by S. DAGLEY (Vol. 59, No. 2 ed.). Sigma Xi, The Scientific Research Society. p. 266.
(14). Pratt, Donald Voet, Judith G. Voet, Charlotte W. (2013). Fundamentals of Biochemistry: Life at the Molecular Level (4th ed.). Hoboken, NJ: Wiley. pp. 441–442. ISBN 978-0470-54784-7.