Functional divergences

Kofod LV, Kauppinen S, Christgau S, Andersen LN, Heldt-Hansen HP, Dorreich K, Dalboge (1994) Cloning and characterization of two structurally and functionally divergent rhamnogalacturonases from Aspergillus aculeatus. J Biol Chem 269 29182-29189... 

The 12-transmembrane-spanning domain topology of the adenylyl cyclase enzymes is similar to that found in the ABC family of transporters (see Ch. 5), which includes the cystic fibrosis transmembrane rectifier and the P-glyco-protein. However, there is currently no convincing evidence of a transporter or channel function for mammalian adenylyl cyclases. The structural similarity may indicate that these functionally divergent protein families are derived in an evolutionary sense from related proteins. 

Li X, Baudry J, Berenbaum MR, Schuler MA (2004) Structural and functional divergence of insect CYP6B proteins from specialist to generalist cytochrome P450. Proc Nat Acad Sci 101 2939-2944... 

Before there can be any extrapolation there must be confidence in the model or rules being used. In practice this often has to involve an element of faith because of lack of validation data, particularly where the rule is empirical. The theory or model should be no more complex than is necessary to fit the data. The accuracy of fit to, for example, a creep curve can often be made more precise by applying ever higher order polynomial expressions, but outside the range of points these functions diverge rapidly to infinity (or minus infinity) leading to predictions that are ridiculous. 

Kovacs M, Wang F, Hu A, Zhang Y, and Sellers JR [2003] Functional divergence of human cytoplasmic myosin II Kinetic characterization of the non-muscle IIA isoform. J Biol Chem 278 38132-38140... 

Obviously, the functions /,( ) diverge at large u, which are not appropriate to represent tip wavefunctions. The functions kiu) are regular at large u, which satisfies the desired boundary condition. Therefore, a component of tip wavefunction with quantum numbers I and m has the general form... 

Schumacher, M.A., Moff, I., Sudanagunta, S.P., Levine, J.D. Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes, J. Biol. Chem., 2000, 275, 2756-2762. 

Helariutta Y, Kotilainen M, Elomaa P, Kalkkinen N, Bremer K, Teeri TH, Albert VA. 1996. Duplication and functional divergence in the chalcone synthase gene family of Asteraceae Evolution with substrate change and catalytic simplification. Proc Natl Acad Sci USA 93 9033-9038. 

CYP2E1 paralogs (see Figure 6.2) both time and functional divergence have worked to drive the human sequences apart. 

Independent of the actual mechanism, functional divergence between two proteins with a common ancestor is exemplified in the /la-barrel structures of N-(phosphor-ibosyl-formimino)-aminoimidazole-carboxamide ribonucleotide isomerase (HisA) and imidazole glycerol phosphate synthase (HisF) of the histidine biosynthetic pathway [16]. The hypothesis of a common origin of the two enzymes was formulated based on sequence comparison [17] and has recently found support by the identification of extensive structural similarities [18],... 

Another consideration that can be applied is observing that the K functions diverge at the center of the reactor (r = 0) and therefore cannot be present in the solution. Taking this into accoimt, we obtain as general solution for any tubular solar reactor... 

Aminoacyl-tRNA synthetases (aaRSs) compose a family of essential enzymes that attach amino acids covalently to tRNA molecules during protein synthesis. Some aaRSs possess a hydrolytic amino acid editing function to ensure the fidelity of protein synthesis. In addition, aminoacylation can occur by indirect pathways that rely on mischarged tRNA intermediates and enzymes other than aaRSs. Throughout evolution, structural and functional divergence of aaRSs has yielded diverse secondary roles. 

Aminoacyl-tRNA synthetases (aaRSs) are critical components of the translation machinery for protein synthesis in every living cell (1). Each aaRS enzyme in this family links a single amino acid covalently to one or more tRNA isoacceptors to form charged tRNAs. Identity elements within the tRNAs serve as molecular determinants or antideterminants that aid in selection by cognate aaRSs (2). Some aaRSs also have an amino acid editing mechanism to clear their mistakes (3). The canonical aaRSs and aaRS-like proteins have functionally diverged to perform many other important roles in the cell (4, 5). Their versatility and adaptability have provided unique opportunities to develop biotechnology tools and to advance medical research. 

I have previously speculated that natural products have functional activity not only because they are part of an organism s natural chemical defences and biological signalling functions, but also because they have been selected to survive the biological environment and are thus bio-available molecules. The combination of chemical defence function, divergent evolution of chemical receptors, and general biological availability, make natural products an especially rich source of functionally active leads. 

J lata. A., Akita, Y, Suzuki, K., and Ohno, S. (1993). Functional divergence of protein kinase C (PKQ family members.. Biol. Cheni. 268,9122-9129-... 

Wang, Y. and X. Gu. Functional divergence in the caspase gene family and altered functional constraints statistical analysis and prediction. Genetics 158 1311-1320, 2001. 

Figure 1. Diversity of Type III PKS catalytic specificity for substrate, number ofpolyketide extension steps, and ring formation. Functional divergence of CHS-like enzymes involves a wide range of acyl-CoA starter molecules and several distinct intramolecular cyclization modes.

Our subsequent comparative structural and mechanistic analyses of the STS and THNS active site cavities and reactions produced results that failed to adhere to this initial model on several counts (4, 5). Neither of these functionally divergent type III PKS active site topologies seemed restrictive enough to enforce a single cyclization-conducive polyketide conformation. In the case of THNS, this mystery was confounded by the biosynthesis of products of quite different size within the same or quite similar active site cavities (5) (See Figure 2). A final indication of the need to revise the existing model was obviated by the apparent mechanistic involvement of chemically reactive residues other than the catalytic triad in both the STS and THNS physiological reactions (4, 5). All... 

This revised model of PKS mechanistic regulation provides an improved framework for studying the functional divergence of evolutionarily related PKS enzymes. Our model posits that alternative product specificities from a given acyl-CoA starter must initially arise due to the selection of some mutation or set of mutations that specifically alters enzymatic reaction partitioning of key intermediates into other competing reaction pathways. Whether this relative kinetic effect is due to an increase or decrease of enzymatic control over the intrinsic reactivity of key intermediates may not be readily apparent from comparing the overall kinetics of evolutionarily refined CHS-like enzymes, as... 

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