Biosynthesis alternative pathways

Two possible pathways for the biosynthesis of 2-AG have been proposed (1) a phospholipase C (PLC) hydrolysis of membrane phospholipids followed by a second hydrolysis of the resulting 1,2-diacylglycerol by diacylglycerol lipase or (2) a phospholipase Ai (PLA,) activity that generates a lysophospholipid, which in turn is hydrolyzed to 2-AG by lysophospholipase C (Fig. 5) (Piomelli, 1998). Alternative pathways may also exist from either triacylglycerols by a neutral lipase activity or lysophosphatidic acid by a dephosphorylase. The fact that PLC and diacylglycerol lipase inhibitors inhibit 2-AG formation in cortical neurons supports the contention that 2-AG is, at least predominantly, biosynthesized by the PLC pathway (Stella, 1997). However, a mixed pathway may also be plausible. 

Marggraf, W.D., and Anderer, F.A., 1974, Alternative pathways in the biosynthesis of phosphatidylserine in mouse cells.Physiol. Chem. 335 1299-1304. 

Biosynthesis of catecholamines. The rate-limiting step, conversion of tyrosine to dopa, can be inhibited by metyrosine (K-methyltyrosine). The alternative pathway shown by the dashed arrows has not been found to be of physiologic significance in humans. However, tyramine and octopamine may accumulate in patients treated with monoamine oxidase inhibitors. 

The terpenes, carotenoids, steroids, and many other compounds arise in a direct way from the prenyl group of isopentenyl diphosphate (Fig. 22-1).16a Biosynthesis of this five-carbon branched unit from mevalonate has been discussed previously (Chapter 17, Fig. 17-19) and is briefly recapitulated in Fig. 22-1. Distinct isoenzymes of 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) in the liver produce HMG-CoA destined for formation of ketone bodies (Eq. 17-5) or mevalonate.7 8 A similar cytosolic enzyme is active in plants which, collectively, make more than 30,000 different isoprenoid compounds.910 However, many of these are formed by an alternative pathway that does not utilize mevalonate but starts with a thiamin diphosphate-dependent condensation of glyceraldehyde 3-phosphate with pyruvate (Figs. 22-1,22-2). 

Figure 22-2 The glyceraldehyde 3-phosphate pyruvate alternative pathway of isoprenoid biosynthesis. The intermediate 1-deoxyxylulose 5-phosphate may enter terpenes, vitamin B6, and thiamin. Isopentenyl diphosphate is shown as the final product, but the intermediate steps are uncertain. See Lange et al 2 ...

Until 1993, all terpenes were considered to be derived from the classical acetate/mevalonate pathway involving the condensation of three units of acetyl CoA to 3-hydroxy-3-methylglutaryl CoA, reduction of this intermediate to mevalonic acid and the conversion of the latter to the essential, biological isoprenoid unit, isopentenyl diphosphate (IPP) [17,18,15]. Recently, a totally different IPP biosynthesis was found to operate in certain eubacteria, green algae and higher plants. In this new pathway glyceradehyde-3-phosphate (GAP) and pyruvate are precursurs of isopentenyl diphosphate, but not acetyl-CoA and mevalonate [19,20]. So, an isoprene unit is derived from isopentenyl diphosphate, and can be formed via two alternative pathways, the mevalonate pathway (in eukaryotes) and the deoxyxylulose pathway in prokaryotes and plant plastids [16,19]. 

The last sequence of reactions in the biosynthesis of choles-terol involves approximately 20 enzymatic steps, starting with lanosterol. In mammals the major route involves a series of double-bond reductions and demethylations (fig. 20.10). The sequence of reactions involves reduction of the A24 double bond, the oxidation and removal of the 14a methyl group followed by the oxidation and removal of the two methyl groups at position 4 in the sterol. The final reaction is a reduction of the A7 double bond in 7-dehydro-cholesterol. An alternative pathway from lanosterol to cholesterol also exists. The enzymes involved in the transformation of lanosterol to cholesterol are all located on the endoplasmic reticulum. 

Wemer, R. A., Rossmann, A., Schwarz, C., Bacher, A., Schmidt, H.-L., and Eisenreich, W., 2004, Biosynthesis of gallic acid in Rhus typhina discrimination between alternative pathways from natural oxygen isotope abundance, Phytochem. 65 2809-2813. 

There is also the possibility that pollutants alter susceptibility of the plant to pathogens (36) or insect attack. Of the latter there is the decreased resistance of ponderosa pine to bark beetle attack caused by ambient oxidant exposure (37). The investigations of others with respect to the effects of fluoride on ponderosa pine indicated that although foliar injury was associated with increased resin exudation pressure, which could be interpreted as an increased capacity of the tree to overcome bark beetle attack, degree of insect infestation was not associated with amount of foliar injury (38). As more is known about pheromones, the botanical investigation of the secondary products of metabolism, such as terpenes and phenolics, may become more important in investigating the mode of action of pollutants in the entire plant. The switch to alternate pathways, while resulting in the same products, may reduce the intermediates needed in biosynthesis and thereby affect the plants resistance to disease or attractiveness to insects. 

The most abundant alkaloid in Coryphantha macromeris, normacromerine, has been shown to originate from tyrosine (330). Tyramine and JV-methyltyramine are efficiently incorporated into normacromerine while octopamine and dopamine are poor precursors. Norepinephrine, epinephrine, normetanephrine, and meta-nephrine have all been shown to be biosynthetically incorporated into normacromerine, and they have also been shown to be naturally occurring trace intermediates in this cactus species (331, 334). Normacromerine is only slowly converted to macromerine in C. macromeris (332). The results indicate that alternative pathways to normacromerine exist precise conclusions regarding the biosynthesis of normacromerine must await further studies. 

Figure 4 The whole A-factor biosynthesis pathway. The major pathway, highlighted by hatching, and an alternative pathway are shown. 

Villand, P., and Kleczkowski, L. A. 1994. Is there an alternative pathway for starch biosynthesis in cereal seeds Z. Naturforsch 49c, 215-219. 

Jain, A.K., and Nessler, C.L., 2000. Metabolic engineering of an alternative pathway for ascorbic acid biosynthesis in plants. Mol. Breeding 6 73-78. 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

---