Genes and Proteins

With the increase in hardware and software, larger systems can be handled with higher accuracy. Much work will continue to be devoted to the study of proteins and polynucleotides (DNA and RNA), and particularly their interactions with more sophisticated methods. Remember proteins and genes are chemical compounds and sophisticated theoretical and chemoinformatics methods should be applied to their study - in addition to the methods developed by bioinfor-maticians. 

The genes encoding many glycosyltransferases have already been cloned, and others are under smdy. Cloning has revealed new information on both protein and gene stmcmres. The latter should also cast light on... 

Rus HG, Vlaicu R, Niculescu F. Interleukin-6 and interleukin-8 protein and gene expression in human arterial atherosclerotic wall. Atherosclerosis 1996 127(2) 263-271. 

Figure 5.15 The filamentous single-stranded DNA bacteriophage fd. Orientation of the proteins and genes in the virion. Note the intergenic space which contains the origin of DNA synthesis. Gene cloning is done in this intergenic space.

Wagner E, Curiel D, Cotten M (1994) Delivery of drugs, proteins and genes into cells using transferrin as a ligand for receptor-mediated endocytosis. Adv Drug Del Rev 14 113-136... 

In contrast to the biopharmaceuticals discussed thus far (recombinant proteins and gene therapy products), antisense oligonucleotides are manufactured by direct chemical synthesis. Organic synthetic pathways have been developed, optimized and commercialized for some time, as oligonucleotides are widely used reagents in molecular biology. They are required as primers, probes and for the purposes of site-directed mutagenesis. 

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NAD(P)H-dependent reduction of 5,10-methylenetetrahydrofolate (CH2-THF) to 5-methyltetrahydrofolate (CH3-THF). CH3-THF then serves as a methyl donor for the synthesis of methionine. The MTHFR proteins and genes from mammalian liver and E. coli have been characterized,12"15 and MTHFR genes have been identified in S. cerevisiae16 and other organisms. The MTHFR of E. coli (MetF) is a homotetramer of 33-kDa subunits that prefers NADH as reductant,12 whereas mammalian MTHFRs are homodimers of 77-kDa subunits that prefer NADPH and are allosterically inhibited by AdoMet.13,14 Mammalian MTHFRs have a two-domain structure the amino-terminal domain shows 30% sequence identity to E. coli MetF, and is catalytic the carboxyterminal domain has been implicated in AdoMet-mediated inhibition of enzyme activity.13,14... 

Measuring both protein and gene expression is important, because evidence is accumulating that the two levels are often not closely correlated. Many other factors besides transcription of the gene are important. These factors include splicing, translation, posttranslational modifications, binding, catabolism, and clearance. Some protein biomarkers will be related to drug action. 

Ho RJY, Gibaldi M. Biotechnology and Biopharmaceuticals Transforming Proteins and Genes into Drugs, Wiley-Liss, Hoboken, NJ, 2003. 

Agresti A, Bianchi ME (2003) HMGB proteins and gene expression. Curr Opin Genet Dev 13 170-178... 

Scientists are developing a number of tools to look at the specific interactions that occur within proteins. As noted above, some deal with the interaction between proteins and genes while others are more general. Section 10.5 dealt with one such approach. 

The actions of cAMP occur almost exclusively via regulation of cAMP-de-pendent protein kinase (PKA), which consists of catalytic and regulatory subunits (Nestler and Duman 1999). There are three different isoforms of the catalytic subunit and four isoforms of the regulatory subunit. In the inactive state, in the absence of cAMP, PKA exists as a dimer of two catalytic and two regulatory subunits. Upon binding of cAMP to the regulatory subunits, the catalytic subunits are released and can phosphorylate substrate proteins. The types of cellular proteins that serve as substrates for PKA include metabohc enzymes, receptors, ion channels, effector proteins, and gene transcription factors. 

COMPARATIVE DRUG DEVELOPMENT OF PROTEINS AND GENES VERSUS SMALL MOLECULES... 

Application of Proteins and Genes as Targets to Accelerate Drug Discovery and Development... 

Biotechnology and biopharmaceuticals transforming proteins and genes into drugs / Rodney J.Y. Ho, Milo Gibaldi. p. cm. 

New precision technology, based on protein structures and function makes it possible for clinicians to detect cancer earlier than ever and provide individualized treatment. Following the discovery of new proteins and gene maps, cancer researchers believed that proteomics is a revolutionary approach to detect cancer and other major illnesses (e.g., HIV) during their early phases and to tailor individualized therapy. 

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