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Enzyme Substrates and Inhibitors

Definition
Enzymes are very efficient catalysts for biochemical reactions. They speed up reactions by providing an alternative reaction pathway of lower activation energy. Enzyme acts on substrate and gives rise to a product. Some substances reduce or even stop the catalytic activities of enzymes are called inhibitors.

Discovery
In 1965, Umezawa H analysed enzyme inhibitors produced by microorganisms and isolated leupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine 3-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine J3-hydroxylase . Recently, an alternative approach has been applied to predict new inhibitors: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors 1. Computer-based methods for identifying inhibitor for an enzyme have been developed, such as molecular mechanics and molecular docking.

Structural Characteristics
The crystal structures of many inhibitors have been determined. The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined. All the three inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism 2.

Emil Fischer in 1894 suggested that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.This is known as "the lock and key" model 3. Daniel Koshland suggested induced fit model where substrate and enzymes are rather flexible structures, the active site is continually reshaped by interactions with the substrate as the substrate interacts with the enzyme 4.

N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The structural analyses of several active-site-mutant enzymes provide a structural basis for the rational design of inhibitors against QC-associated disorders 5.

Mode of Action
Enzymes are proteins that catalyze chemical reactions. Enzymes interact with substrate and convert them into products. Inhibitor binding can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. There are a variety of types of inhibitors including: nonspecific, irreversible, reversible - competitive and noncompetitive. Reversible inhibitors bind to enzymes with non-covalent interactions like hydrophobic interactions, hydrogen bonds, and ionic bonds. Non-specific methods of inhibition include any physical or chemical changes which ultimately denature the protein portion of the enzyme and are therefore irreversible. Specific Inhibitors exert their effects upon a single enzyme. Most poisons work by specific inhibition of enzymes. A competitive inhibitor is any compound which closely resembles the chemical structure and molecular geometry of the substrate. The inhibitor may interact with the enzyme at the active site, but no reaction takes place. A noncompetitive inhibitor is a substance that interacts with the enzyme, but usually not at the active site.  The net effect of a non competitive inhibitor is to change the shape of the enzyme and thus the active site, so that the substrate can no longer interact with the enzyme to give a reaction. Non competitive inhibitors are usually reversible. Irreversible Inhibitors form strong covalent bonds with an enzyme.  These inhibitors may act at, near, or remote from the active site .

Functions
Industrial application, enzymes are widely used commercially, for example in the detergent, food and brewing industries. Protease enzymes are used in 'biological' washing powders to speed up the breakdown of proteins in stains like blood and egg. Problems using enzymes commercially include: they are water soluble which makes them hard to recover and some products can inhibit the enzyme activity (feedback inhibition) .

Drug molecules, many drug molecules are enzyme inhibitors and a medicinal enzyme inhibitor is usually characterized by its specificity and its potency. A high specificity and potency suggests that a drug will have fewer side effects and less toxic. Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry 6.

Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known.

Nerve gases such as diisopropylfluorophosphate (DFP) inhibit the active site of acetylcholine esterase by reacting with the hydroxyl group of serine to make an ester.

References

  1. Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.

  2. Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.

  3. Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.

  4. Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.

  5. Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.

  6. Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

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Product Name Catalog # Unit Price/Unit 
2A/2B Dengue Protease Substrate
Ac-RTSKKR-pNA
10996-01 1 mg $250 cart inquire
2B/3, Dengue Protease Substrate
Ac-EVKKQR-pNA
10995-01 1 mg $250 cart inquire
3/4A, Dengue Protease Substrate
Ac-FAAGRK-pNA
10994-01 1 mg $250 cart inquire
Activated Protein C (390 - 404), human
YGVYTKVSRYLDWIH
11007-01 1 mg $230 cart inquire
Cathepsin G (77 - 83)
HPQYNQR
10993-01 1 mg $210 cart inquire
Cathepsin S Substrate
Ac-KQKLR-AMC
11005-01 1 mg $116 cart inquire
Dok - 4 (130 - 145)
GVQCEQTDRFNVFLLP
11014-01 1 mg $250 cart inquire
Dok - 4 (263 - 275)
LPRSAYWHHITGS
11013-01 1 mg $220 cart inquire
Dok - 5 (263 - 275)
LPRSAYWQHITRQ
11011-01 1 mg $220 cart inquire
Dok - 6 (263 - 275)
LPRSAYWHHITRQ
11009-01 1 mg $220 cart inquire
H - Ala - Arg - Arg - AFC
ARR-AFC
10982-01 1 mg $275 cart inquire
H - Ala - Leu - Lys - AMC
ALK-AMC
10975-01 1 mg $270 cart inquire
H - Ala - Phe - Lys - AMC
AFK-AMC
10976-01 1 mg $250 cart inquire
H - D - Val - Leu - Arg - AFC
vLR-AFC
10988-01 1 mg $275 cart inquire
H - D - Val - Leu - Lys - AFC
vLK-AFC
10986-01 1 mg $275 cart inquire
H - Glu - Ala - Ala - Phe - AFC
EAAF-AFC
10981-01 1 mg $280 cart inquire
H - Gly - Pro - AMC
GP-AMC
10978-01 1 mg $250 cart inquire
HJ Inhibitor Peptide 2
KWWCRW
10997-01 1 mg $205 cart inquire
H - Tyr - Val - Ala - Asp - AFC
YVAD-AFC
10980-01 1 mg $380 cart inquire
MeOSuc - Ala - Ala - Pro - Val - AFC
MeOSuc-AAPV-AFC
10990-01 1 mg $310 cart inquire
NubO (68–75), Ndufa4 (68–75)
VNVDYSKL
11004-01 1 mg $210 cart inquire
Nuclear Export Signal, NES, Dok - 1 (348 - 359)
LLKAKLTDPKED
11010-01 1 mg $210 cart inquire
proFIX18
TVFLDHENANKILNRPKR
11000-01 1 mg $240 cart inquire
proFIX28
TVFLDHENANKILNRPKRYNSGKLEEFV
11001-01 1 mg $340 cart inquire
Proprotein Convertase Substrate, PC4, Mca - labele
Ac-KTKQLR-MCA
11016-01 1 mg $270 cart inquire
proPT18
HVFLAPQQARSLLQRVRR
11002-01 1 mg $240 cart inquire
proPT28
HVFLAPQQARSLLQRVRRANTFLEEVRK
11003-01 1 mg $345 cart inquire
pro - ε - Tx1X/12
LKRTIRTRLNIR
10998-01 1 mg $220 cart inquire
Transglutaminase Substrate, biotinylated
Biotin-TVQQEL
11015-01 1 mg $250 cart inquire
ε - TxIX12
ECCEDGWCCTAA
10999-01 1 mg $245 cart inquire
(Z - Phe - Arg)2Rh110
(Z-FR)2Rh110
10992-01 1 mg $390 cart inquire

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