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Enzyme activity must be regulated so that the proper levels of products are produced at all times and places This control occurs in several ways: - biosynthesis at the genetic level - covalent modification after biosynthesis - regulatory enzymes - feedback inhibition A common covalent enzyme modification is the addition or removal of a phosphate group - under high-energy conditions (high ATP and low ADP), phosphorylation is favored - under low-energy conditions (low ATP and high ADP), dephosphorylation is favored - this regulates the balance between biosynthesis and catabolism
Zymogens
Zymogens (proenzymes) are inactive forms of enzymes They are activated by removal of peptide sections For example, proinsulin is converted to insulin by removing a 33-amino acid peptide chain
Digestive Enzymes
Digestive enzymes are produced as zymogens, and are then activated when needed Most of them are synthesized and stored in the pancreas, and then secreted into the small intestine, where they are activated by removal of small peptide sections The digestive enzymes must be stored as zymogens because otherwise they would damage the pancreas
Allosteric Enzymes
An allosteric enzyme binds a regulator molecule at a site other than the active site (an allosteric site) Regulators can be positive or negative: - a positive regulator enhances the binding of substrate and accelerates the rate of reaction. - a negative regulator prevents the binding of the substrate to the active site and slows down the rate of reaction (non-competitive inhibition)
Feedback Control
In feedback control, a product acts as a negative regulator When product concentration is high, it binds to an allosteric site on the first enzyme (E1) in the sequence, and production is stopped When product concentration is low, it dissociates from E1 and production is resumed Feedback control allows products to be formed only when needed
Enzyme Cofactors
A simple enzyme consists only of protein in its active form Other enzymes are active only when they combine with cofactors such as metal ions or small molecules - a cofactor that is a small organic molecule, such as a vitamin, is called a coenzyme
A Zinc Carboxypeptidase
A Zn2+ ion in the active site of carboxypeptidase A promotes hydrolysis of a C-terminal amino acid from a polypeptide by interacting with the carbonyl oxygen The Zn2+ activates the carbonyl in a similar way as an acid catalyst
Functions of Coenzymes
Coenzymes are small organic molecules that are often required to prepare the active site for proper substrate binding and/or participate in catalysis Because they are not destroyed during the reaction, coenzymes are only required in small quantities
Fat soluble vitamins are stored in the body, so should not be consumed in excess, as they can be toxic at high levels
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Folic acid (folate) consists of pyrimidine, p-aminobenzoic acid (PABA) and glutamate It forms the coenzyme THF used in the synthesis of nucleic acids A deficiency can lead to abnormal red blood cells, anemia, poor growth, hair loss and depression Dietary sources include green leafy vegetables, beans, meat, seafood, yeast, asparagus and whole grains Some derivatives of folic acid, such as methotrexate, are inhibitors of the enzyme that converts folic acid to THF - these are used as anti-cancer drugs, especially for leukemias
Vitamin A
Vitamin A can exist as an alcohol (retinol), an aldehyde (retinal) or a carboxylic acid (retinoic acid) In the retina of the eye, retinol undergoes cis-trans isomeration as part of photoreception Vitamin A is also involved in synthesis of RNA and glycoproteins A deficiency in vitamin A can lead to night blindness, depressed immune response and growth inhibition Dietary sources include yellow and green fruits and vegetables Beta-carotenes are converted to vitamin A in the liver
H3C CH3 CH3 Beta-carotene CH3 H3C
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CH3
H3C
CH3
H3C
CH3
CH3
Vitamin D
Vitamin D (D3) is synthesized from 7-dehydrocholesterol in skin exposed to sunlight It regulates the absorption of phosphorus and calcium during bone growth A deficiency in vitamin D can result in weakened bones Dietary sources include cod liver oil, egg yolk, and vitamin D enriched foods (such as milk)
Vitamin E
Vitamin E (-tocopherol) acts as an antioxidant in cells Not much is know about its mechanism, but it may prevent the oxidation of unsaturated fatty acids A deficiency of vitamin E can lead to anemia Dietary sources include meat, nuts, vegetable oils, whole grains, and vegetables Synthetic vitamin E is a mixture of the alpha and beta forms (enantiomers) - only the alpha form can be utilized by our cells
CH3 HO CH3 H3C CH3 O CH3 CH3 CH3 CH3
Vitamin K
Vitamin K1 (in plants) has a saturated side chain Vitamin K2 (in animals) has a long unsaturated side chain Vitamin K2 is needed for the synthesis of zymogens for blood clotting A deficiency of vitamin K can lead to extended bleeding from small cuts and increased bruising Dietary sources include meat, spinach and cauliflower
O CH3 CH3 O CH3 CH3
Vitamin K1 (phylloquinone)
Vitamin K2 (menaquinone)