Norcoclaurine

One step in the biosynthesis of morphine is the reaction of dopamine with p-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. Assuming that the reaction is acid-catalyzed, propose a mechanism. 

Fig. 10.8 Selected cDNAs isolated in recent years that encode enzymes involved in the biosynthesis of various classes of isoquinoline alkaloids. 6-OMT, norcoclaurine 6-0-methyltransferase 23 CYP80A1, berbamunine synthase 19 CYP80B1, (S)-A-methylcoclaurine 3 -hydroxylase 20 CPR, cytochrome P-450 reductase 29 4 -OMT, (5)-3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase 30 BBE, berberine bridge enzyme 12 SalAT, salutaridinol 7-O-acetyltransferase 28 COR, codeinone reductase.25...

Non-depolarizing alkaloids 185 Non-natural alkaloids 6 Non-protein derived alkaloids 93, 94 Noradrenaline 110, 112, 187 Norbelladine 94, 110 Norcoclaurine 7, 176 Norephedrine 10 Norepinephrine 171, 194 Norevoninate alkaloids 108, 109... 

Fig. 18 Reconstructed isoquinoline alkaloid biosynthetic pathway in microbes (E. coli and S. cerevisiae) [120]. Accession numbers of the genes can be taken from Gene Bank. C3,4-DHPA-A 3,4-dihydroxyphenylacetaldehyde NCS norcoclaurine synthase 60MT 6-0-methyltransferase CNMT coclaurine-/V-mcthyltransferase 4 OMT 4 -0-methyltransferase BBE berberine bridge enzyme NMT /V-methyltransferase)...

The three cDNAs of norcoclaurine-6-O-methyltransferase, coclaurine-AA methyltransferase and 3 -hydroxy-AAmethylcoclaurine 4,-<9-methyltransferase converting (R, S)-norlaudanosoline into (R, Sj-reticuline with a 5-10% yield... 

Ounaroon, A., G. Decker, J. Schmidt, F. Lottspeich and T.M. Kutchan, (R,S)-Reticuline 7-O-methyltransferase and (R,S)-Norcoclaurine 6-O-Methyltransferase of Papaver... 

Gene regulation represents the most basic level of metabolic control. Although there are few examples in the alkaloid literature, the post-translational regulation of enzymes can also exert considerable influence over the control of metabolic flux. Recent work in our laboratory suggests that enzymatic controls function of the regulation in alkaloid biosynthesis. (5)-Norcoclaurine is accepted as the central precursor to all BAs produced in plants.6,7 However, NCS was first isolated based on its ability to convert dopamine and 3,4-dihydroxyphenylacetaldehyde (3,4-DHPAA) to the tetrahydroxylated alkaloid (S)-norlaudanosoline.129 The ability of NCS to accept either 4-HPAA or 3,4-DHPAA contributed to the incorrect conclusion that (S)-norlaudanosoline is a common pathway intermediate. However, only (5)-norcoclaurine has been detected in plants. 

Figure 7.8 Schematic representation of the putative reaction mechanism for norcoclaurine synthase. A. 4-Hydroxyphenyl-acetaldehyde (black circles) binds to the enzyme. B. The binding of dopamine (gray squares) to one subunit of the enzyme increases the dopamine binding affinity of the second subunit. C. A second molecule of dopamine binds to the enzyme. The enzyme undergoes a conformational change (dark gray) during the reaction. D. The product, (5)-norcoclaurine, is released. E. The enzyme reverts to a conformation to which 4-HPAA can bind. F. A new reaction sequence begins.

STADLER, R., KUTCHAN, T.M., ZENK, M.H., Norcoclaurine is the central intermediate in benzylisoquinoline alkaloid biosynthesis. Phytochemistry, 1989, 28,1083-1086. 

LOEFFLER, S, ZENK, M.H, The hydroxylation step in the biosynthetic pathway leading from norcoclaurine to reticuline. Phytochemistry, 1990,29,3499-3503. 

SAMANANI, N., FACCHINI, P.J., Isolation and partial characterization of norcoclaurine synthase, the first committed step in benzylisoquinoline alkaloid biosynthesis, from opium poppy. Planta, 2001,213, 898-906. 

With the assumption that reticulines are also precursors in mammalian synthesis of morphine, it was challenging to investigate whether they could be produced by enzymatic reactions similar to those utilized in benzylisoquinoline-producing plants (274). This plan focused attention on reactions controlled by the enzyme catechol 0-methyltransferase (COMT), using 5-adenosyl-L-methionine (SAM) for the methylation reaction. Mammalian COMT is present in mammalian tissues, particularly the liver, and an enzyme preparation from rat liver was used for the experiments. It was found that (S)-norcoclaurine, which is the first isoquinoline produced in benzylisoquinoline-producing plants, was similarly O-methylated in vitro by SAM in the presence of COMT, and a reverse proportion of methylated products was obtained with the (/ )-enantiomer (277). Similar 0-methylation of (5)-4 -demethylreticuline (3 -hydroxy-N-methylcoclaurine), prepared by total synthesis (162), however, afforded almost exclusively (5)-orientaline, with a methoxy group at C-3 and not at C-4 as in (5)-reticuline (Fig. 37) (762). 

As a result of research over the past 20 years (Facchini, 2001 Ziegler et al, 2006 Sato et al, 2007 Zenk and Juenger, 2007 Liscombe and Facchini, 2008 Ziegler and Facchini, 2008), it is now clear that the first committed step in the biosynthesis of isoquinoline is the formation of (S)-norcoclaurine (Fig. 2.5). This alkaloid is an important precursor of a variety of pathways that lead to a series of diverse structures within this alkaloid group. 

Investigations of a number of enzymes involved in tyrosine conversion have suggested that the first committed step in the biosynthesis of benzylisoquinolines involves a Picfef-Spengler-type condensation of dopamine with 4-hydroxyphenylacetaldehyde (which derived from tyrosine) to give (S)-norcoclaurine, a compound that has proved to be pivotal in the formation of all benzylisoquinoline alkaloids (Fig. 2.5). The condensafion sfep is cafalysed... 

Figure 2.5 Formation of (5)-reticuline. NCS, norcoclaurine synthase 60MT, 6-hydroxy-O-methyltransferase CNMT, coclaurine N-methyltransferase 40MT, 4 hydroxy-0-methyltransferase.

S)-Reticuline is readily formed from (S)-norcoclaurine as a result of a series of hydroxylations and methylations. From intermediates observed in vivo and enzyme studies, it may be concluded that (S)-norcoclaurine is... 

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