Editing Saxitoxin (section)

== Biosynthesis ==

Although the [[biosynthesis]] of saxitoxin seems complex, organisms from two different [[kingdom (biology)|kingdoms]], indeed two different [[Domain (biology)|domains]], species of marine [[dinoflagellate]]s and freshwater cyanobacteria are capable of producing these toxins. While the prevailing theory of production in dinoflagellates was through symbiotic [[Mutualism (biology)|mutualism]] with cyanobacteria, evidence has emerged suggesting that dinoflagellates themselves also possess the [[genes]] required for saxitoxin synthesis.<ref name="Stüken, et. al., 2011">{{cite journal|last1=Stüken|first1=Anke|last2=Orr|first2=Russell|last3=Kellmann|first3=Ralf|last4=Murray|first4=Shauna|last5=Neilan|first5=Brett|last6=Jakobsen|first6=Kjetill|title=Discovery of Nuclear-Encoded Genes for the Neurotoxin Saxitoxin in Dinoflagellates|journal=PLOS ONE|date=18 May 2011|volume=6|issue=5|page=e20096|doi=10.1371/journal.pone.0020096|pmid=21625593|pmc=3097229|bibcode=2011PLoSO...620096S|doi-access=free}}</ref>

Saxitoxin biosynthesis is the first non-terpene [[alkaloid]] pathway described for bacteria, though the exact mechanism of saxitoxin biosynthesis is still essentially a theoretical model. The precise mechanism of how [[Substrate (chemistry)|substrates]] bind to [[enzyme]]s is still unknown, and genes involved in the biosynthesis of saxitoxin are either putative or have only recently been identified.<ref name="Stüken, et. al., 2011"/><ref name="Kellman, 2008">{{Cite journal | last1 = Kellmann | first1 = R. | last2 = Mihali | first2 = T. K. | last3 = Jeon | first3 = Y. J. | last4 = Pickford | first4 = R. | last5 = Pomati | first5 = F. | last6 = Neilan | first6 = B. A. | doi = 10.1128/AEM.00353-08 | title = Biosynthetic Intermediate Analysis and Functional Homology Reveal a Saxitoxin Gene Cluster in Cyanobacteria | journal = Applied and Environmental Microbiology | volume = 74 | issue = 13 | pages = 4044–4053 | year = 2008 | pmid = 18487408| pmc =2446512 | bibcode = 2008ApEnM..74.4044K }}</ref>

Two biosyntheses have been proposed in the past. Earlier versions differ from a more recent proposal by Kellmann, et al. based on both biosynthetic considerations as well as genetic evidence not available at the time of the first proposal. The more recent model describes a STX gene cluster (Sxt) used to obtain a more favorable reaction. The most recent reaction sequence of Sxt in cyanobacteria<ref name="Kellman, 2008" /> is as follows. Refer to the diagram for a detailed biosynthesis and intermediate structures.

[[Image:Saxitoxin Biosynthesis.PNG|thumb|600px|class=skin-invert-image|Biosynthesis|alt= The proposed biosynthetic pathway of saxitoxin in cyanobacteria]]
# It begins with the loading of the [[acyl carrier protein]] (ACP) with acetate from [[acetyl-CoA]], yielding intermediate 1.
# This is followed by SxtA-catalyzed methylation of acetyl-ACP, which is then converted to propionyl-ACP, yielding intermediate 2. 
# Later, another SxtA performs a [[Claisen condensation]] reaction between propionyl-ACP and [[arginine]] producing intermediate 4 and intermediate 3. 
# SxtG transfers an amidino group from an arginine to the α-amino group of intermediate 4 producing intermediate 5. 
# Intermediate 5 then undergoes retroaldol-like condensation by SxtBC, producing intermediate 6. 
# SxtD adds a double bond between C-1 and C-5 of intermediate 6, which gives rise to the 1,2-H shift between C-5 and C-6 in intermediate 7.
# SxtS performs an [[epoxidation]] of the double bond yielding intermediate 8, and then an opening of the epoxide to an [[aldehyde]], forming intermediate 9. 
# SxtU reduces the terminal aldehyde group of the STX intermediate 9, thus forming intermediate 10. 
# SxtIJK catalyzes the transfer of a carbamoyl group to the free hydroxyl group on intermediate 10, forming intermediate 11. 
# SxtH and SxtT, in conjunction with SxtV and the SxtW gene cluster, perform a similar function which is the consecutive hydroxylation of C-12, thus producing saxitoxin and terminating the STX biosynthetic pathway.