Substrate analog

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Substrate analogs (substrate state analogues), are chemical compounds with a chemical structure that resemble the substrate molecule in an enzyme-catalyzed chemical reaction. Substrate analogs can act as competitive inhibitors of an enzymatic reaction. An example is phosphoramidate to the Tetrahymena group I ribozyme [1] Other examples of substrate analogs include 5’-adenylyl-imidodiphosphate, a substrate analog of ATP, and 3-acetylpyridine adenine dinucleotide, a substrate analog of NADH. [2]

As a competitive inhibitor, substrate analogs occupy the same binding site as its analog, and decrease the intended substrate’s efficiency. [3] The maximum rate (Vmax) remains the same [4] while the intended substrate’s affinity (measured by the Michaelis constant KM) is decreased. [5] This means that less of the intended substrate will bind to the enzyme, resulting in less product being formed. In addition, the substrate analog may also be missing chemical components that allow the enzyme to go through with its reaction. This also causes the amount of product created to decrease.

Substrate analogs usually bind to the binding site reversibly. This means that the binding of the substrate analog to the enzyme’s binding site is non-permanent. The effect of the substrate analog can be nullified by increasing the concentration of the originally intended substrate. [6] There are also substrate analogs that bind to the binding site of an enzyme irreversibly. If this is the case, the substrate analog is called an inhibitory substrate analog, a suicide substrate, or a Trojan horse substrate. [7] An example of a substrate analog that is also a suicide substrate/Trojan horse substrate is penicillin, which is an inhibitory substrate analog of peptidoglycan. [8]

Some substrate analogs can still allow the enzyme to synthesize a product despite the enzyme’s inability to metabolize the substrate analog. These substrate analogs are known as gratuitous inducers. [9] An example of a substrate analog that is also a gratuitous inducer is IPTG (isopropyl β-D-1-thiogalactopyranoside), a substrate analog and gratuitous inducer of β-galactosidase activity. [10]

See also

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Enzyme Large biological molecule that acts as a catalyst

Enzymes are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and the field of pseudoenzyme analysis recognizes that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

Active site Active region of an enzyme

In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate and residues that catalyse a reaction of that substrate. Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes.

Furanose

A furanose is a collective term for carbohydrates that have a chemical structure that includes a five-membered ring system consisting of four carbon atoms and one oxygen atom. The name derives from its similarity to the oxygen heterocycle furan, but the furanose ring does not have double bonds.

Cofactor (biochemistry) Non-protein chemical compound or metallic ion

A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst. Cofactors can be considered "helper molecules" that assist in biochemical transformations. The rates at which these happen are characterized in an area of study called enzyme kinetics. Cofactors typically differ from ligands in that they often derive their function by remaining bound.

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Enzyme catalysis Catalysis of chemical reactions by specialized proteins known as enzymes

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Transition state analogs, are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Enzymes interact with a substrate by means of strain or distortions, moving the substrate towards the transition state. Transition state analogs can be used as inhibitors in enzyme-catalyzed reactions by blocking the active site of the enzyme. Theory suggests that enzyme inhibitors which resembled the transition state structure would bind more tightly to the enzyme than the actual substrate. Examples of drugs that are transition state analog inhibitors include flu medications such as the neuraminidase inhibitor oseltamivir and the HIV protease inhibitors saquinavir in the treatment of AIDS.

Aralkylamine <i>N</i>-acetyltransferase

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In enzymology, chorismate mutase is an enzyme that catalyzes the chemical reaction for the conversion of chorismate to prephenate in the pathway to the production of phenylalanine and tyrosine, also known as the shikimate pathway. Hence, this enzyme has one substrate, chorismate, and one product, prephenate. Chorismate mutase is found at a branch point in the pathway. The enzyme channels the substrate, chorismate to the biosynthesis of tyrosine and phenylalanine and away from tryptophan. Its role in maintaining the balance of these aromatic amino acids in the cell is vital. This is the single known example of a naturally occurring enzyme catalyzing a pericyclic reaction. Chorismate mutase is only found in fungi, bacteria, and higher plants. Some varieties of this protein may use the morpheein model of allosteric regulation.

Fluorocitric acid Chemical compound

Fluorocitric acid is a fluorinated carboxylic acid derived from citric acid by substitution of one hydrogen by a fluorine atom. The appropriate anion is called fluorocitrate. Fluorocitrate is formed in two steps from fluoroacetate. Fluoroacetate is first converted to fluoroacetyl-CoA by acetyl-CoA synthetase in the mitochondria. Then fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate. This step is catalyzed by citrate synthase. Flurocitrate is a metabolite of fluoroacetic acid and is very toxic because it is not processable using aconitase in the citrate cycle. The enzyme is inhibited and the cycle stops working.

Competitive inhibition Interruption of a chemical pathway

Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected by this principle, but several classes of competitive inhibition are especially important in biochemistry and medicine, including the competitive form of enzyme inhibition, the competitive form of receptor antagonism, the competitive form of antimetabolite activity, and the competitive form of poisoning.

References

  1. ↑ Hanna, Raven L.; Gryaznov, Sergei M.; Doudna, Jennifer A. (2000-11-01). "A phosphoramidate substrate analog is a competitive inhibitor of the Tetrahymena group I ribozyme". Chemistry & Biology. 7 (11): 845–854. doi: 10.1016/S1074-5521(00)00033-8 . ISSN   1074-5521. PMID   11094338.
  2. ↑ Stein, Ross L. Kinetics of Enzyme Action: Essential Principles for Drug Hunters. Hoboken, NJ: John Wiley, 2011. Print. p185. ISBN   9780470414118
  3. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
  4. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
  5. ↑ Cannon, Joseph G. Pharmacology for Chemists. Oxford: Oxford UP, 2007. Print. p70. ISBN   9780841239272
  6. ↑ Cannon, Joseph G. Pharmacology for Chemists. Oxford: Oxford UP, 2007. Print. p70. ISBN   9780841239272
  7. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
  8. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
  9. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
  10. ↑ Garrett, Reginald H.; Grisham, Charles M. (2013). Biochemistry (5th ed. ed.). Belmont, CA: Brooks/Cole, Cengage Learning. p. 108. ISBN   9781133106296
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