Pyrophosphate transfer

Chehade, K.A.H., et al. (2002). Photoaffinity analogues of farnesyl pyrophosphate transferable by protein farnesyl transferase. J Am Chem Soc 124 8206-8219. 

In higher mammalian organisms, thiamine is transformed to the coenzyme thiamine pyrophosphate by direct pyrophosphate transfer from ATP. This coenzyme performs important metabolic functions, for example, as cocarboxylase in the decarboxylation of rr-keto acids (such as pyruvate to form acctyl-CoA) and in tran.sketolases (such as use of pentoses in the hexose monophosphate shunt). 

Transketolase, which requires thiamine pyrophosphate, transfers two-carbon units (Figure 5-33). 

ATP metabolic energy, phosphate-, pyrophosphate transfer, adenylation ... 

Pyruvate may enter the Krebs cycle by a pathway different from that involving the formation of acetyl-CoA. Indeed, the keto acid can be converted to a dicarboxylic acid by at least two different biochemical processes. One of them involves the carboxylation of pyruvic acid leading to the formation of oxaloacetic acid. The actual substrate in that reaction is not pyruvic acid, but phosphoenolpyruvic acid. The enzyme involved requires manganese, and IDP acts as the phosphorus acceptor. The reaction is coupled with the pyrophosphate transfer (catalyzed by nucleoside diphosphokinase) from ITP to ADP. 

The mechanism of this reaction is probably similar to that of reaction (70) except for the site of the nucleophilic attack. In pyrophosphate transfer (Eq. (73)] the central P atom of ATP, rather than the outer terminal P atom, is attacked. 

Subsequent knowledge of the stmcture, function, and biosynthesis of the foHc acid coenzyme gradually allowed a picture to be formed regarding the step in this pathway that is inhibited by sulfonamides. The biosynthetic scheme for foHc acid is shown in Figure 1. Sulfonamides compete in the step where condensation of PABA with pteridine pyrophosphate takes place to form dihydropteroate (32). The amino acids, purines, and pyrimidines that are able to replace or spare PABA are those with a formation that requkes one-carbon transfer catalyzed by foHc acid coenzymes (5). 

The first step of this reaction, decarboxylation of pyruvate and transfer of the acetyl group to lipoic acid, depends on accumulation of negative charge on the carbonyl carbon of pyruvate. This is facilitated by the quaternary nitrogen on the thiazolium group of thiamine pyrophosphate. As shown in (c), this cationic... 

The transport of each COg requires the expenditure of two high-energy phosphate bonds. The energy of these bonds is expended in the phosphorylation of pyruvate to PEP (phosphoenolpyruvate) by the plant enzyme pyruvate-Pj dikinase the products are PEP, AMP, and pyrophosphate (PPi). This represents a unique phosphotransferase reaction in that both the /3- and y-phosphates of a single ATP are used to phosphorylate the two substrates, pyruvate and Pj. The reaction mechanism involves an enzyme phosphohistidine intermediate. The y-phosphate of ATP is transferred to Pj, whereas formation of E-His-P occurs by addition of the /3-phosphate from ATP ... 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

A number of lyases are known which, unlike the aldolases, require thiamine pyrophosphate as a cofactor in the transfer of acyl anion equivalents, but mechanistically act via enolate-type additions. The commercially available transketolase (EC 2.2.1.1) stems from the pentose phosphate pathway where it catalyzes the transfer of a hydroxyacetyl fragment from a ketose phosphate to an aldehyde phosphate. For synthetic purposes, the donor component can be replaced by hydroxypyruvate, which forms the reactive intermediate by an irreversible, spontaneous decarboxylation. 

The V(V) oxidation is about 10 and 10 times slower than those by Mn(ril) sulphate and pyrophosphate respectively. The [V(V)] dependence indicates two concerted one-equivalent oxidations one possible mechanism involves oxygen-transfer, viz. 

The end phosphate adds water and is transferred onto another compound, causing thereby the phosphorylation of the latter. An alternative route for the phosphate bond energy release is exemplified by pyrophosphate cleavage of ATP ... 

Similarly, cyclodextrin accelerates the cleavage of pyrophosphates by about 200-fold. This enhancement is associated with a simultaneous transfer of a phenylphosphate group to the host by the vicinal action of the hydroxy groups [see Figure 5.4] (Hennrich Cramer, 1965). In this case the product monophenylphosphate also forms an inclusion complex and thus product inhibition occurs. Because of this, the system is not truly catalytic. 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

Bacitracin (Fig. 4) is a cyclic peptide antibiotic. The lipid II molecule involved in the bacterial cell wall biosynthesis has a C55 isoprenyl pyrophosphate moiety that must be dephosphorylated so that it can reparticipate in another round of lipid II transfer. Bacitracin binds to the isoprenyl pyrophosphate and prevents the dephosphorylation which, in turn, blocks cell wall growth by interfering with the release of the muropeptide subunits to the outside of the bacterial cell membrane. Bacitracin inhibits similar reactions in eukaryotic cells. So, it is systemically toxic but is an effective and widely used topical antibiotic. 

This enzyme [EC 2.5.1.40] catalyzes the conversion of trms,trans-fainesyl diphosphate (or, trans,trans-farnesyl pyrophosphate) to aristolochene and diphosphate (or, pyrophosphate). The enzyme-catalyzed reaction proceeds through an initial internal transfer of the farnesyl... 

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