Phenanthrene (fungal 9R,10R) Pathway Map

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This pathway was contributed by Jun Ouyang and Meaghan Fitzgerald, University of Minnesota.

Polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene are commonly found as pollutants in soils, estuarine waters and sediments, and other terrestrial and aquatic sites. Phenanthrene has been shown to be toxic to marine diatoms, gastropods, mussels, crustaceans, and fish. Phenanthrene has a fused-ring structure resembling higher molecular weight carcinogenic PAHs, and has received interest as a useful model PAH for mammalian and fungal studies.

In general, bacteria that utilize phenanthrene as the sole source of carbon and energy oxidize it via a dioxygenase primarily in the "bay-region" to form a phenanthrene cis-dihydrodiol. In contrast to these bacteria, Streptomyces flavovirens and the marine cyanobacterium Agmenellum quadruplicatum metabolize phenanthrene in the "K-region", mainly to phenanthrene trans-9,10- dihydrodiol with a 9S,10S absolute configuration similar to that produced by mammalian enzymes.

Besides the bacterial metabolic pathways of phenanthrene , fungi are also able to biotransform phenanthrene. Unlike bacteria, fungi do not utilize phenanthrene as the sole source of carbon and energy but, instead cometabolize the PAH to hydroxylated products. Many nonligninolytic fungi metabolize phenanthrene in a highly redio- and stereoselective manner, via cytochrome P-450 monooxygenase and epoxide hydrolase, to form phenanthrene trans-1,2-, trans-3,4, and trans-9,10-dihydrodiol; 1-, 2-, 3-, 4-, and 9-phenanthrols; and sulfate, glucoside, and glucuronide conjugates of primary metabolites. The fungi are known to biotransform phenanthrene to trans-dihydrodiol metabolites that are generally the mirror images of the corresponding trans-dihydrodiols obtained from rat liver microsomes. Although the 1,2-, 3,4-position ("bay-region") of phenanthrene is the main site of enzymatic attack, fungi are also able to transform phenanthrene at the 9,10-position ( "K-region"), which is a major site of mammalian enzymatic attack. The metabolic pathways and biochemical reaction mechanisms for the biotransformation of phenanthrene by these fungi closely resemble phase I (oxidation) and subsequent phase II (conjugation) metabolic pathways documented for terrestrial and aquatic animals. Cytochrome P-450, epoxide hydrolase, UDP-glucuronyltransferase, glycosyltransferase, and aryl-sulfotransferase activities have been demonstrated to be involved in the oxidation and subsequent conjugation of phenanthrene.

1-phenanthryl-beta-D-glucopyranoside and a novel phenanthrene glucoside conjugate, 2-hydroxy-1-phenanthrylbeta- D-glucopyranoside were produced by C. elegans ATCC 9245. The possible mechanism could involve two intermediates: trans-1,2-dihydrodiol and its dehydrogenated product 1,2-dihydroxyphenanthrene. 1-methoxyphenanthrene was identified only in A. niger van Tieghem (strain b52, DSM 11167) via methylation (Thomas et al., 1997).

The five phenanthrols 1-, 2-, 3-, 4-, and 9-phenanthrol were most likely produced by rearrangement of the postulated arene oxides (reactions: A, H, B, C, and D). After oxidative step in reaction E, a ring cleavage reaction may be involved in the enzymatic attack at C-9 and C-10 positions of 9,10-phenanthrenequinone to form 2,2'-diphenate in reaction F and eventually CO2 by mineralization (reaction G). The enzyme catalyzed step F has not been identified.

The white rot fungus Pleurotus ostreatus produces trans-9R,10R-dihydrodiol phenanthrene as the principal enantiomer, which is different from that of the the principal eneantiomer produced by Phanerochaete chrysosporium. P. ostreatus can further cleave the aromatic ring and form 2,2'-diphenic acid and carbon dioxide. Ligninolytic Phanerochaete chrysosporium has been demonstrated to metabolize phenanthrene in a similar way to that of Pleurotus ostreatus (see: Phenanthrene (fungal 9S,10S) Pathway); however different enantiomers are produced in the first metabolic step in the two fungi.

The following is a text-format Phenanthrene pathway map. Organisms which can initiate the pathway are given, but other organisms may also carry out later steps. Follow the links for more information on compounds or reactions.

 
               Graphical Map (24K) and Graphical Map (21K)                                          Graphical Map (10K) 
           |--------------------------------------------------|                                  |----------------------|

                             Phenanthrene                                                               Phenanthrene
                     Pleurotus ostreatus
                   Syncephalastrum racemosum UT-70                                                           |  
                  Cunninghamella elegans ATCC 9245                                                           | 
                                  |                                                                          | 
                                  |                                                                          | phenanthrene
             +--------------------+-------------------------+                                                | 9,10-
             |                    |                         |                                                | monooxygenase
             |                    |                         |                                                |
             | phenanthrene       | phenanthrene            | phenanthrene                                   v
             | 3,4-               | 9,10-                   | 1,2-                                     [Phenanthrene
             | monooxygenase      | monooxygenase           | monooxygenase                 +----------  9,10-oxide]
             |                    |                         |                               |                | 
             v                    v                         v                               v                |      
+----- [Phenanthrene-       [Phenanthrene- ----------+[Phenanthrene-                      to the             | phenanthrene
|        3,4-oxide] -----+    9,10-oxide]            |  1,2-oxide]  ------> Phenanthrene (bacterial) Pathway | 9,10-epoxide
|       /                |        |                  |      |                   and Phenanthrene fungal      | hydrolase 
|      /                 |        |                  |      |                      (9S,10S)  Pathway         |
|      | phenanthrene    |        | phenanthrene     |      |                                                v
|      | 3,4-epoxide     |        | 9,10-epoxide     |      |                    only in                   trans-
|      | hydrolase       |        | hydrolase        |      |                   C. elegans           9R,10R-Dihydrodiol-
|      v                 |        |                  |      |                   ATCC 9245               phenanthrene
|    trans-              |        |                  |      +-----------------+--------------+               |
|3,4-Dihydrodiol-        |        v                  |      | C               |              |               |
| phenanthrene           |      trans-               |      v                 |              | phenanthrene  | 
|  |   |                 | 9R,10R-Dihydrodiol-       |2-Phenanthrol           |              | 1,2-epoxide   | trans-
|  |   | trans-          |   phenanthrene            |      |                 |              | hydrolase     | 9R,10R-, 
+--+   | 3,4-Dihydrodiol-|        |                  |      |                 |              |               | dihydrodiol
|      | phenanthrene    |        | trans-9R,10R-    |      | 2-phenanthrol   |              |               | phenanthrene
|      | sulfotransferase|        | dihydrodiol-     |      | sulfotransferase|              v               | dehydrogenase
|      |                 |        | phenanthrene     |      |                 |           [trans-            |
|      v                 |        | sulfotransferase |      |                 |       1,2-Dihydrodiol-       |
| Phenanthrene           |        v                  |      |                 |      +-phenanthrene]         v
|3,4-dihydrodiol-        |   Phenanthrene            |      v                 |      |       |       [9,10-Dihydroxy-
|   sulfate              | 9,10-dihydrodiol-         |2-Phenanthryl-          |      v       | trans-  phenanthrene]
|  conjugate             |     sulfate               |   sulfate              |    to the    | 1,2-          |
|                        |    conjugate              |                        | Phenanthrene | dihydrodiol   | 
|                        |                           |                        |    fungal    | phenanthrene  | 
|        +---------------+------+                    +-->       to the        |   (9S,10S)   | dehydrogenase | E
|        |                      |                    |       Phenanthrene     |    Pathway   |               |        
|        | A                    | H                  |   (bacterial) Pathway  |              |               |
|        |                      |                    | and Phenanthrene fungal|       [1,2-Dihydroxy-        |
|        v                      v                    |    (9S,10S)  Pathway   |        phenanthrene]         |
|  3-Phenanthrol          4-Phenanthrol              |            ^           |              |               v 
|        |                      |                    | B          |           |              |      [9,10-Phenanthrene-
|        |                      |                    |            |           |              |            quinone]      -->  to the  
|        | 3-phenanthrol        | 4-phenanthrol      |            |           |              | 1,2-dihydroxy-|             Phenanthrene
|        | sulfotransferase     | sulfotransferase   |            |           |              | phenanthrene  |                fungal
|        |                      |                    v            |           |              | glycosyl-     v F             (9S,10S)
|        |                      |              9-Phenanthrol -----+           |              | transferase   |                Pathway
|        |                      |                    |            |           |              |               |                   ^
|        v                      v                    |            |           |              |               v                   |
|  3-Phenanthryl-         4-Phenanthryl-             |            |           |              |         2,2'-Diphenate  ----------+      
|     sulfate                sulfate                 |            |           | D            |               |     
|                                                    |            |           |              |               |      
+-----+                               9-phenanthrol  |            |           |              |               |    
      |                            sulfotransferase  |            |           |              v               v G    
      |           9-Phenanthryl- <-------------------+            +--- [1-Phenanthrol]   2-Hydroxy-          |    
      |              sulfate                         |                        |        1-phenanthryl-        |    
      |                               9-phenanthrol  |                        |           beta-D-            |
      v                +          UDP-glucuronosyl-  |                        |       glucopyranoside        v    
    to the                              transferase  |                        |                             CO2          
 Phenanthrene     9-Phenanthryl- <-------------------+                        |             
    fungal      beta-D-glucuronide                                            |              
   (9S,10S)                                                                   |
   Pathway                                                                    |
                                                                              |
                                                                              |
                                                                1-phenanthrol |
                                                          glycosyltransferase |
                                            1-Phenanthryl- <------------------+
                                                 beta-                        |
                                           D-glucopyranoside                  |
                                                                              | 
                                                  +             1-phenanthrol |   
                                                             sulfotransferase |
                                            1-Phenanthryl-  <-----------------+
                                               sulfate                        |
                                                                              |
                                                                              | 
                                                                1-phenanthrol |   
                                                            methyltransferase |
                                      1-methoxy- <----------------------------+
                                     phenanthrene  only in A.niger van Tieghem
                                                    (strain b52, DSM 11167)



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Page Author(s): Jun Ouyang and Meaghan Fitzgerald

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