TIM barrels

Fig. 6. Distribution of the most common folds in selected bacterial, archaeal, and eukaryotic proteomes. The vertical axis shows the fraction of all predicted folds in the respective proteome. Fold name abbreviations FAD/NAD, FAD/NAD(P)-binding Rossman-like domains TIM, TIM-barrel domains SAM-MTR, S-adenosylmethionine-dependent methyltransferases PK, serine-threonine protein kinases PP-Loop, ATP pyrophosphatases. mge, Mycoplasma genitalium rpr, Rickettsiaprowazekii hh x, Borrelia burgdorferi ctr, Chlamydia trachomatis hpy, Helicobacter pylori tma, Thermotoga maritima ssp, Synechocystis sp. mtu, Mycobacterium tuberculosis eco, Escherichia coli mja, Methanococcus jannaschii pho, Pyrococcus horikoshii see, Saccharomyces cerevisiae, cel, Caenorhabditis elegans.

In each of the three divisions of life, the most common fold is the P-loop NTPase. Four common folds, namely P-loop NTPases, Triose Phosphate Isomerase (TIM) barrels, ferredoxin-like domains, and Rossmann-fold domains, are see in the top-10 lists for all three divisions (Table IV). 

Wise EL, Rayment I. 2004. Understanding the importance of protein structure to nature s routes for divergent evolution in TIM barrel enzymes. Acc Chem Res 37 149-158. 

The crystal structure of a pentamer of GlcNAc residues, representing the chitin polymer (poly-/l-(l-4)-GlcNAc), boimd to the chitinase enzyme ChiB from Serratia marcescens, revealed a narrow, timnel-like active site in the center of the TIM barrel fold [167]. Several conserved residues near the center of the site, which are important in catalysis, interact with the substrate via hydrogen bonds, while interactions farther from the center depend on van der Waals interactions. The sugar in the - 1 subsite adopts a boat conformation, presumably due to interactions with these critical active-site residues. 

Figure 3. Model of (p a)s TIM barrel from triose phosphate isomerase. Numbered arrow and twisted ribbon structures are beta sheets and alpha helicies, respectively. (Adapted and reproduced from Ref. 66 with permission. Cop3night 1984 American Association for the Advancement of Science.)...

Branden CL The TIM barrel—the most frequently occurring folding motif in proteins. Curr Opin Struct Biol 1991 1 978-983. 

Figure 13-6 Stereoscopic view into the active site of triose phosphate isomerase showing side chains of some charged residues PGH, a molecule of bound phosphoglycolohydroxamate, an analog of the substrate enolate.138 The peptide backbone, as an alpha-carbon plot, is shown in light lines.147 The (a/ (S)8-barrel structure is often called a TIM barrel because of its discovery in this enzyme. Courtesy of M. Karplus.

The enzyme triosephosphate isomerase, abbreviated to TIM, was found to have an important type of structure, now called an a//3 or TIM barrel, consisting of at least 200 residues. In its idealized form, the barrel consists of eight parallel /3 strands connected by eight helixes (Figure 1.19). The strands form the staves of the barrel while the helixes are on the outside and are also parallel (Figure 1.20). (3 strands 1 and 8 are adjacent and form hydrogen bonds with each other. The center of the barrel is a hydrophobic core composed of the side chains of alternate residues of the strands, primarily those of the branched... 

As already discussed in Chapter 11, there are more than 10 000 protein structures known but only about 30 3D structure types. This might be traced to a limited number of possible stable polypeptide structures but most probably reflects the evolutionary history of the diversity of proteins. There are structural motifs which repeat themselves in a multitude of enzymes which are otherwise neither structurally nor functionally related, such as TIM barrel proteins, four-helix bundle proteins, Rossmann folds, or a/j3-folds of hydrolases (Figure 16.1). 

The study of //J-barrel proteins, also called TIM barrels after the first enzyme investigated in this class, triose phosphate isomerase, or (/3a)8-barrel enzymes after the... 

J. M. Thornton, One fold with many functions The evolutionary relationships between TIM barrel families based on their sequences, structures and functions,... 

Figure 7.9 Topological structures of a-amylase A. Two-dimensional representation of the secondary and domain structures of porcine pancreatic a-amylase. Alpha helices are represented as circles and (3-strands in the up-direction as squares, and in the down direction as double squares. The (a/(3)g—TIM barrel comprises domain A. Hydrogen bonds between (3-strands are shown by dashed lines. The a-helices and (3-strands are identified in the various domains by A, B and C. (Reprinted by permission ofthe authors M. Qian et al.120) Two-dimensional representation ofthe secondary and domain structures of barley malt a-amylase (AMY2-2). Alpha helices are represented as cylinders and (3-strands as arrows. The (a/(3)g—TIM barrel comprises domain A, with eight (3-strands and an equivalent of eight a-helices. The active-site is composed ofthe loops that connect the C-termini ofthe (3-strands to the N-termini ofthe peripheral a-helices. (Adapted from A. Kadziola et al.121)...

Figure 7.11 Topological comparison ofthe (a/(3) —TIM barrel structure ofthe a-amylases (A) and the a/a-barrel structure of glucoamylase (B). a-Helices are represented as circles and (3-strands as squares. (From Aleshin et al. 147 reprinted by permission)...

Like transketolase, transaldolase (TA, E.C. 2.2.1.2) is an enzyme in the oxidative pentose phosphate pathway. TA is a class one lyase that operates through a Schiff-base intermediate and catalyzes the transfer of the C(l)-C(3) aldol unit from D-sedoheptulose 7-phosphate to glyceraldehyde-3-phosphate (G3P) to produce D-Fru 6-P and D-erythrose 4-phosphate (Scheme 5.59). TA from human as well as microbial sources have been cloned.110 111 The crystal structure of the E. coliu and human112 transaldolases have been reported and its similarity to the aldolases is apparent, since it consists of an eight-stranded (o /(3)s or TIM barrel domain as is common to the aldolases. As well, the active site lysine residue that forms a Schiff base with the substrate was identified.14112 Thus, both structurally and mechanistically it is related to the type I class of aldolases. 

In principle, nature has decoupled protein function and protein fold. The most commonly known example for a fold conveying a broad variety of functions is the TIM barrel. First found in triosephosphate isomerase, the TIM barrel also occurs in proteins as diverse as aldose reductase, enolase, and adenosine deaminase (see, e.g., the review by Nagano et al. [104]). To date, the TIM barrel fold, as a generic scaffold, is associated with 15 different types of enzymatic functions. 

The existence of -barrels was established for chymotrypsin at a very early stage in the now common protein crystal structure analyses. This enzyme contains two distorted six-stranded -barrels with identical topologies (Birktoft and Blow, 1972). A selection of -barrels in water-soluble proteins is given in Table I. The very abundant TIM-barrel consisting of eight parallel /1-strands was also detected rather early (Banner et al., 1975). Additional eight-stranded /1-barrels of this group are those of streptavidin (Hendrickson et al., 1989) and of the lipocalins (Newcomer et al., 1984). 

---