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Unformatted text preview: 8-1Cell and Molecular Biology (Biol. Chem. 410A)Lecture #8Harry R. Matthews, Ph.D.October 7, 1996Control by Covalent ModificationClinical correlations:cholesterol synthesisoncogenes in breast and prostate cancercancer: growth factor signalingLearning objectives:serine/threonine phosphatetyrosine phosphatecascade amplificationthe MAP kinase cascadeintracellular protein degradationOptional reading:Alberts et al. 3rd ed. Chapter 5, pp. 195-202. Chapter 15, pp. 760-768.holesterol synthesis is controlled to a large extent by phosphorylation and de-phosphorylation of HMG-CoA reductase, a covalent modification. Similarly, protein kinases and phosphatases comprise many on-cogenes and partake in growth factor signal-ing, a component of most cancers.CWe have seen, in the case of digestive en-zymes, how the synthesis of zymogens can al-low enzymes to be transported in an inactive state and activated where required. Zymogens can also be used to provide a reservoir of in-active proteins that will be activated when re-quired (like flushing a lav-atory cistern). This will be studied in more detail in discussion of the formation and dissolution of blood clots in lecture 10. Zymo-gens are an important ex-ample of control by covalent modification. We have also seen how al-losteric control can provide feedback regulation to maintain order in the body and respond to its needs. Allosteric control is not an example of covalent modific-ation since the allosteric regulators bind directly and non-covalently. Allosteric control is reversible and the analogous type of regulation by covalent modification is the reversible modification of amino acid side-chains. Some enzymes are affected directly by both types of control. By far the most common of these modifications is the phosphorylation of serine and threonine but tyrosine phosphorylation is also a key part of many control mechanisms, including cancer and the activation of T cells in immunology. This type of modification is discussed below. Many other types of protein modification occur, some reversible, some irre-versible.outsidecytoplasmPPPgrb-2sosrasrafMAP KKMAP KPPPPPPMAP KAPrskFigure 8-1. MAP kinase Cascade.8-2Reversible Covalent Modification of EnzymesThe reversible covalent modific-ation of enzymes is important in control of metabolism, cell pro-liferation, response to hormones and other processes. Examples of the types of reversible side-chain modifications found in cells include:a. phosphorylation of amino acid side-chains, serine, threonine, histidine and tyrosineb. ADP-ribosylation (adenosine diphosphori-bosylation) of amino acid side-chains (tentatively identified as arginine and...
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- Spring '03