Biologically Active Natural Products - ACS Publications - American

Chapter 13

Naturally Occurring Carbon—Phosphorus Compounds as Herbicides

Downloaded by UNIV OF MASSACHUSETTS AMHERST on March 7, 2016 | http://pubs.acs.org Publication Date: November 28, 1988 | doi: 10.1021/bk-1988-0380.ch013

Robert E. Hoagland Southern Weed Science Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Stoneville, MS 38776

Since the discovery in 1959 of the first naturally occurring compound containing a covalent C-P bond (2-aminoethylphosphonic acid, AEP), many phosphonate-related compounds have been identified in living systems. Some information on distribution, metabolic pathways and chemical properties exists, but no precise role for these compounds is known. In the early 1970's, the importance of some natural and synthetic phosphonates and their biological activity (e.g., antibiotics, herbicides) was recognized. The most successful synthetic phosphonate herbicide is glyphosate [N-(phosphonomethyl)glycine]. Bialaphos (L-2-amino-4-[(hydroxy)(methyl)phosphinoyl] butyryl-L-alanyl-L-alanine), isolated from Streptomyces viridochromogenes, was discovered and reported as an antibiotic (1972),and later found to be herbicidal. Phosalacine, a bialaphos analog, has been isolated from Kitasatosporia phosalacinea. Peptidases cleave amino acid moieties from the latter two compounds yielding the active component phosphinothricin whose site of action is inhibition of glutamine synthetase in plants. This compound is being marketed as the herbicide glufosinate. The biosynthetic pathway for bialaphos and the cloning and characterization of genes that code for these conversions have recently been elucidated. Naturally occurring compounds with potential for use as herbicides have recently become of great interest to weed scientists and agricultural chemists. This interest may be attributed to the facts that natural phytotoxins (1) have a co-evolved species specificity, (2) often have diverse chemistries that could lead to completely novel synthetic herbicides, (3) may have low mammalian toxicity and pose less of a biohazard because they are specific and more biodegradable than many commercial herbicides, and (4) may also be less costly to register as herbicides by regulatory agencies such as EPA. Furthermore, microbial plant pathogens may be directly used to control weeds, and two microorganism products currently are This chapter not subject to U.S. copyright Published 1988 American Chemical Society

Cutler; Biologically Active Natural Products ACS Symposium Series; American Chemical Society: Washington, DC, 1988.


13. HOAGLAND

Carbon—Phosphorus Compounds as Herbicides

183

c o m m e r i c a l l y a v a i l a b l e f o r weed c o n t r o l (1). T h i s has g e n e r a t e d i n t e r e s t i n t o x i n s produced by t h e s e pathogens as p e s t i c i d e s . Many n a t u r a l l y o c c u r r i n g p h y t o t o x i c compounds have been found t o be produced by h i g h e r p l a n t s , b a c t e r i a , f u n g i , and a n i m a l s . An e x c e l l e n t r e v i e w o f h e r b i c i d e s from some o f t h e s e n a t u r a l s o u r c e s has r e c e n t l y been p u b l i s h e d ( 2 ) . The f o c u s o f t h i s c h a p t e r w i l l be t o examine some o f t h e n a t u r a l l y o c c u r r i n g phosphonate compounds ( i . e . , b i a l a p h o s , p h o s a l a c i n e , and p h o s p h i n o t h r i c i n ) w i t h r e s p e c t t o t h e i r n a t u r a l s o u r c e s , b i o c h e m i s t r y , and b i o l o g i c a l p r o p e r t i e s . Special reference i s g i v e n t o t h e i r use and/or p o t e n t i a l use as h e r b i c i d e s , i n c l u d i n g t h e i r r e l a t i o n s h i p t o some s y n t h e t i c phosphonates t h a t have been examined f o r b i o l o g i c a l a c t i v i t y . D i s c o v e r y o f Carbon-Phosphorus Compounds i n Nature Phosphorus i s r e q u i r e d f o r t h e growth and r e p r o d u c t i o n o f a l l p l a n t s and a n i m a l s . O r g a n i c phosphorus compounds i n t h e form o f o r t h o p h o s p h a t e s a r e i n v o l v e d i n t h e s e many l i f e p r o c e s s e s and a r e contained i n basic biochemical constituents ( i . e . , proteins, c a r b o h y d r a t e s , n u c l e i c a c i d s , and p h o s p h o l i p i d s ) . They a r e a l s o used i n t h e g e n e r a t i o n o f h i g h energy bonds, p r o v i d e b u f f e r i n g c a p a c i t y , and t h e phosphate m o i e t y i m p a r t s water s o l u b i l i t y t o t h e s e compounds ( 3 ) . In s p i t e o f t h e m u l t i t u d e o f compounds o c c u r r i n g as o r t h o p h o s p h a t e - o x y g e n compounds ( e s t e r s , d i e s t e r s , and p h o s p h o r i c a c i d a n h y d r i d e s ) , some organophosphate compounds o c c u r i n n a t u r e w i t h carbon-phosphorus bonds; i . e . , phosphonates. These compounds had been c o n s i d e r e d as p o s s i b l e n a t u r a l l y o c c u r r i n g compounds by Chavane (4) as e a r l y as 1947, b u t a c t u a l i d e n t i f i c a t i o n o f t h e f i r s t phosphonate i n a l i v i n g system d i d n o t o c c u r u n t i l 1959 when H o r i g u c h i and Kandatsu (5) found 2 - a m i n o e t h y l p h o s p h o n i c a c i d (AEP, F i g u r e 1) i n an amino a c i d h y d r o l y s a t e from rumen p r o t o z o a l l i p i d . Over t h e p a s t 30 y e a r s , numerous r e p o r t s have shown t h e p r e s e n c e o f AEP and o t h e r phosphonates i n a wide range o f organisms, i n c l u d i n g b a c t e r i a , p r o t o z o a , c o e l e n t e r a t e s , m o l l u s c s , and u n i c e l l u l a r p l a n t s . D e t e c t i o n o f Phosphonates The c h e m i s t r y o f phosphonates has d e v e l o p e d r e l a t i v e l y s l o w l y compared t o t h a t o f p h o s p h a t e s . T h i s i s due t o t h e f a c t t h a t t h e carbon-phosphorus bond i s d i f f i c u l t t o s y n t h e s i z e and because o f t h e v a s t amount o f i n f o r m a t i o n on and d i s t r i b u t i o n o f phosphate and orthophosphate e s t e r s . F u r t h e r m o r e , e a r l y s t u d i e s on n a t u r a l phosphonates were slow due t o t h e l a c k o f s e n s i t i v e methodology f o r d e t e c t i o n o f t h e carbon-phosphorus bond. These e a r l y s t u d i e s c o n s i s t e d m o s t l y o f v a r i o u s c h r o m a t o g r a p h i c and i s o l a t i o n techniques. E a r l y a n a l y t i c a l methods f o r t h e d e t e c t i o n o f AEP i n b i o l o g i c a l m a t e r i a l s have been r e v i e w e d ( 6 ) . The p r o c e d u r e s u s u a l l y i n v o l v e d ion-exchange chromatography f o r t h e s e p a r a t i o n o f AEP f o l l o w e d by d e t e c t i o n u s i n g n i n h y d r i n . Various chromatographic m o d i f i c a t i o n s o f t h e s e p r o c e d u r e s have been expanded by s e v e r a l r e s e a c h e r s (7-10). More r e c e n t l y , g a s - l i q u i d chromatography and mass s p e c t r o m e t r y have been employed f o r aminophosphonate determination (11-13). Use o f t h e s e l a t t e r two t e c h n i q u e s o f t e n r e q u i r e s d e r i v i t i z a t i o n (14-16). I s o t a c h o p h o r e s i s has a l s o been used t o a n a l y z e aminophosphonates ( 1 7 ) . The use o f s o p h i s t i c a t e d t e c h n i q u e s such as NMR has made a n a l y s i s o f t i s s u e s and t i s s u e


184

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e x t r a c t s more r a p i d and s e n s i t i v e . NMR has been used by a number o f r e s e a r c h e r s f o r m e a s u r i n g phosphonates i n t i s s u e e x t r a c t s (18-21), v a r i o u s b i o l o g i c a l f l u i d s (22, 23), whole c e l l s (24, 25), and s o i l (26). B i o s y n t h e s i s and M e t a b o l i s m o f AEP Phosphonates can undergo v a r i o u s b i o c h e m i c a l t r a n s f o r m a t i o n s which i n v o l v e s y n t h e s i s o r c a t a b o l i s m o f t h e carbon-phosphorus bond, or t h a t p r o c e e d l e a v i n g the C-P bond i n t a c t . This l a t t e r category i n c l u d e s s y n t h e s i s and d e g r a d a t i o n r e a c t i o n s o f p h o s p h o n o l i p i d s , phosphonopeptides, o t h e r complex compounds, and N - m e t h y l a t i o n and t r a n s a m i n a t i o n (27, 28). B e f o r e 1983, e n z y m a t i c c o n v e r s i o n o f p h o s p h o e n o l p y r u v a t e t o 3-phosphonopyruvate v i a i n t r a m o l e c u l a r phosphate-phosphonate rearrangement i n v o l v i n g P O H m i g r a t i o n from oxygen t o c a r b o n was g e n e r a l l y a c c e p t e d (29-34). However, t h e enzyme r e s p o n s i b l e f o r t h i s has not been i s o l a t e d and characterized. In 1983 a l k y l p h o s p h i n o u s a c i d s were d e t e r m i n e d as p r e c u r s o r s o f aminophosphonates ( i n c l u d i n g p h o s p h i n o t h r i c i n ) and a n o v e l pathway o f C-P bond b i o s y n t h e s i s was p r o p o s e d which i n v o l v e s a r e d u c t i o n o f the phosphate t o p h o s p h i t e e s t e r p r i o r t o rearrangement o f p h o s p h o e n o l p y r u v a t e (35-37) ( F i g u r e 2 ) . Reduced 3-phosphonopyruvate may t h e n be o x i d i z e d t o 3-phosphonopyruvate o r d i r e c t l y undergo t r a n s f o r m a t i o n s l e a d i n g t o v a r i o u s a l k y l p h o s p h o n a t e compounds. Confirmation of t h i s proposal requires i s o l a t i o n of r e d u c e d 3-phosphonopyruvate and t h e enzymes i n v o l v e d . D e t a i l s on some o f t h e s e b i o s y n t h e t i c t r a n s f o r m a t i o n s have r e c e n t l y been r e p o r t e d and w i l l be p r e s e n t e d l a t e r i n the s e c t i o n c o n c e r n i n g s y n t h e s i s of bialaphos. a

a

The use o f l a b e l e d p r e s u r s o r s o f AEP i n i n t a c t c e l l s and c e l l - f r e e e x t r a c t s o f Tetrahymena showed t h a t AEP was formed from p h o s p h o n o e n o l p y r u v a t e v i a 3-phosphonopyruvate, but the e x a c t mechanism o f 3-phosphonopyruvate c o n v e r s i o n t o AEP was u n c l e a r . P r e s e n t l y two pathways a r e p r o p o s e d as summarized i n F i g u r e 3. One p r o p o s a l s u g g e s t s a m i n a t i o n f o l l o w e d by d e c a r b o x y l a t i o n o f 3-phosphonoalanine ( 3 1 ) . A second mechanism s u g g e s t s d e c a r b o x y l a t i o n as t h e f i r s t s t e p f o l l o w e d by phosphonoacetaldehyde a m i n a t i o n ( 3 3 ) . Both pathways may be o p e r a t i v e i n some systems (33). B i o s y n t h e s i s o f p h o s p h o n o l i p d s and N-methylated d e r i v a t i v e s have been r e v i e w e d e l s e w h e r e (38, 3 9 ) . D e t a i l s o f c a t a b o l i c r o u t e s o f n a t u r a l phosphonates have not been e x t e n s i v e l y examined e x c e p t f o r AEP and 3-phosphonalanine. In b a c t e r i a AEP i s degraded i n a two-step p r o c e s s i n v o l v i n g t r a n s a m i n a t i o n whereby AEP donates i t s amino group t o p y r u v a t e and i s c o n v e r t e d t o phosphonoacetaldehyde ( F i g u r e 4) (40-43). R e c e n t l y , an enzyme r e s p o n s i b l e f o r t h i s t r a n s a m i n a t i o n s t e p has been p u r i f i e d t o homogeneity from Pseudomonas a e r u g i n o s a ( 4 4 ) . O c c u r r e n c e and D i s t r i b u t i o n o f

Phosphonates

AEP and o t h e r phosphonates have been found i n a wide d i v e r s i t y o f l i v i n g organisms; but t h e s e p l a n t , a n i m a l , and m i c r o b i a l s o u r c e s r e p r e s e n t o n l y a minute f r a c t i o n o f t h e t o t a l l i v i n g organisms. The t r u e e x t e n t o f t h e d i s t r i b u t i o n o f t h e s e compounds i s confounded by (1) the l a c k o f complete s u r v e y s w i t h i n and among s p e c i e s , (2) t h e use o f i n s e n s i t i v e t e c h n i q u e s f o r d e t e c t i o n , and (3) t h e



13. HOAGLAND


0 II H N~CH -CH -P-0H 2

2

2

OH Figure

1.

COOH 0 I

II

C-Q-P-OH II

CH

COOH 0

reduction

I

II

C-Q-P-OH II

I

2

of 2-aminoethylphosphonate

Structure

OH

CH

I

2

(AEP).

0 II

Rearranr gement

C-COOH 1

H

CH I

further transforations

2

H-P-OH II

0 Figure

2.

P r o p o s e d pathway

f o r C-P b o n d

biosynthesis.


185


NH 0 0 I transamiH decarboxy- U HOOC-C-H — HOOC-C C-H I nation I lation I CH CH CH


2

2

2

2

P03H

P0gH

2

2

transami nation

decarbo xylation CH NH 2

2

CH I P0aH

minor pathway

major pathway

2

2

CH I

2

Ρ0Λ

2

AEP F i g u r e 3.

CH2NH

AEP

Biosynthesis of 2 aminoethylphosphonate

pyruvate \ 2-aminoethylphosphonate

(AEP)

alanine 2-Phosphonoacetaldehyde HpO

p y r i d o x a l phosphate

r acetaldehyde + P i F i g u r e 4. Degradation of 2-aminoethylphosphonate B a c i l l u s cereus.

(AEP)


by


13.

HOAGLAND

Carbon-Phosphorus Compounds as Herbicides

187

d i s t r i b u t i o n o f phosphonates v i a f o o d c h a i n s t o organisms l a c k i n g biosynthesis routes f o r these materials. T a b l e I summarizes t h e d a t e and s o u r c e o f i s o l a t i o n o f v a r i o u s n a t u r a l l y - o c c u r r i n g phosphonate compounds. Compounds l i s t e d h e r e a r e aminophosphonates, but o t h e r phosphonates which a r e not s u b s t i t u t e d amines have been found. These i n c l u d e t h e a n t i b i o t i c s phosphomycin, phosphazomycin A, and phosphazomycin B; t h e phosphinous a c i d , 2 - h y d r o x y - 2 - c a r b o x y - e t h y l p h o s p h i n a t e ; and oxophosphonates. These oxophosphonates have been shown t o be i n t e r m e d i a t e s i n t h e b i o s y n t h e s i s o f AEP and β-phosphonalanine ( 3 7 ) . Phosphonates u s u a l l y r e p r e s e n t a s m a l l p o r t i o n o f t h e t o t a l phosphorus c o n t e n t o f i n d i v i d u a l s p e c i e s . F o r example, i n f r a c t i o n s o f s e v e r a l marine a n i m a l s , phosphonate p e r c e n t a g e s ranged from 0.16 t o 0.75* o f t o t a l phosphorus ( 5 0 ) . Arainophosphonic a c i d s i s o l a t e d from p l a n k t o n r e p r e s e n t e d 3* o f t h e t o t a l phosphorus c o n t e n t ( 5 1 ) . Phosphonate s t u d i e s i n b a c t e r i a s u g g e s t low l e v e l s ; i . e . , l e s s t h a n 1* o f t o t a l phosphorus (7, 9, 52-55). Phosphonates i n p r o t o z o a a s s o c i a t e d w i t h t h e a l i m e n t a r y t r a c t i n r u m i n a n t s a r e i n t h e range o f s e v e r a l p e r c e n t o f t o t a l phosphorus, but i n o t h e r p r o t o z o a , such as E u g l e n a g r a c i l i s , t h e l e v e l i s 0.10* o f t o t a l phosphorus (53) t o 15* i n T e t r a l y m e n a p y r i f o r m i s ( 1 4 ) . T. p y r i f o r m i s c o n t a i n s r e l a t i v e l y h i g h l i p i d c o n c e n t r a t i o n s i n microsomes and c i l i a (56, 57); and due t o i t s h i g h phosphonate c o n t e n t and ease o f l a b o r a t o r y c u l t u r e , t h i s organism has been used i n many s t u d i e s p e r t a i n i n g t o the b i o c h e m i s t r y o f AEP and l i p i d s c o n t a i n i n g AEP. The phylum C o e l e n t e r a t a has been shown t o c o n t a i n many organisms w i t h phosphonate compounds, some w i t h l e v e l s up t o 50* o f t o t a l phosphorus ( 5 0 ) . Phosphonate o c c u r r e n c e i n o t h e r i n v e r t e b r a t e s i s limited. AEP has, however, been d e t e c t e d i n t h r e e E c h i n o d e r m a t a [two s p e c i e s o f s t a r f i s h (50, 58) and a s e a u r c h i n ( 5 9 ) , and i n one s p e c i e s each o f Nemathelminthes ( 5 3 ) , S p o n g i a ( 5 9 ) ] , and Anne1ides (59) . S e v e r a l a r t h r o p o d s (marine c r u s t a c e a n s ) a l s o c o n t a i n AEP (8). The h i g h e s t l e v e l o f AEP i n l i v i n g t i s s u e y e t r e p o r t e d i s i n s n a i l ( H e l i s o m i a sp) eggs where n e a r l y a l l phosphorus o c c u r s as phosphonate phosphorus and 85* o f t h i s i s AEP ( 2 4 ) . The I s o l a t i o n o f AEP from t i s s u e s o f v a r i o u s r u m i n a t i n g c h o r d a t e s , i n c l u d i n g b r a i n (60) , m i l k ( 6 1 ) , l i v e r ( 6 2 ) , b i l e ( 6 3 ) , b l o o d ( 6 4 ) , and sperm (64) have s u g g e s t e d t o some r e s e a r c h e r s t h a t t h e aminophosphonates p r e s e n t a r e r e l e a s e d by d i g e s t i o n o f p r o t o z o a . Phosphonates have a l s o been found i n n o n - r u m i n a t i n g mammals, i n c l u d i n g r a t ( 1 2 ) , g u i n e a p i g ( 6 5 ) , and man (66, 6 7 ) . AEP has been d e t e c t e d i n human t i s s u e s such as b r a i n , l i v e r , s k e l e t a l muscle, and h e a r t i n amounts o f 0.01, 0.02, 0.04, and 0.06* o f wet w e i g h t , r e s p e c t i v e l y ( 1 1 ) . Phosphonate d i s t r i b u t i o n i n t h e p l a n t kingdom I s a p p a r e n t l y l i m i t e d t o t h e lower f u n g i and u n i c e l l u l a r p l a n t s , but as mentioned p r e v i o u s l y , s u r v e y s a r e i n c o m p l e t e . AEP has been d e t e c t e d i n marine p h y t o p l a n k t o n (68, 51) and i n a fungus, Pythium p r o l a t u m ( 6 9 ) . Enzyme I n h i b i t i o n by V a r i o u s Phosphonate Compounds. The e a r l i e s t r e p o r t o f enzyme i n h i b i t i o n by phosphonate compounds was t h e r e p o r t o f g l u t a m i n e s y n t h e t a s e (GS) i n h i b i t i o n by p h o s p h o n i c a n a l o g s o f g l u t a m i c a c i d ( 7 0 ) . S i n c e t h e n , numerous r e p o r t s have i n d i c a t e d i n t e r a c t i o n s o f phosphonates w i t h many d i f f e r e n t enzymes. T a b l e I I i s a c o m p i l a t i o n o f some enzymes which show i n v i t r o i n h i b i t i o n by v a r i o u s s u b s t i t u t e d phosphonates. S i n c e phosphonates i n h i b i t a wide


Cutler; Biologically Active Natural Products ACS Symposium Series; American Chemical Society: Washington, DC, 1988. a n t i b i o t i c FR-33289 a n t i b i o t i c FR-32863 -

3-(N-acetyl-N-hydroxyamino)-2hycroxypropylphosphonate

3-(N-formyl-N-hydroxyamino)1-t-propenylphosphonate

2-hydroxyphenyl -1-ami noethy1 phosphonate

2-aminoethylphosphinate

2-amino-2-carboxyethyl

3-amino-3-carboxy-propyl(phosphonate)

-

fosmidomycin

3-(Ν-acyl-N-hydroxyami n o ) p r o p y l phosphonate

phosphonate

a n t i b i o t i c FR-900098

-

4-carboxy-4-amino-2-t-butenyl phosphonic a c i d

3-(N-acetyl-N-hydroxyamino)propyl phosphonate

-

2-ami no-1-hydroxyethylphosphonate

phosphinothricin

-

3-amino-3-carboxy-propyl (methylphosphonate)

-

-

2-(N,N,N-trimethyl-2-aminoethyl phosphonate

phosphonate

phosphonate

2-(N,N-dimethyl)2-aminoethyl phosphonate

2-(N-methyl)2-aminoethyl

2-carboxy-2-aminoethyl

0-phosphonoalanine

c i l i a t i n e (AEP)

2-aminoethyl

phosphonate

Common Name

Chemical Name

Aminophosphonates

(1967)

(1967)

(1973)

(1972)

37

StreDtomvces h v a r o s c o D i c u s

(1983)

37

37

27

49

49

49

49

18

48

47

46

46

StreDtomvces h v a r o s c o D i c u s (1983)

StreDtomvces h v a r o s c o D i c u s (1983)

A c t i n o m v c e t e s s t r a i n K-26 (1982) Actinomadura S D i c u l o s o s D o r a

StreDtomvces l a v e n d u l a e (1981)

StreDtomvces r u b e l l o m u r i n u s subsD. i n d i a o f e r u s (1981)

StreDtomvces l a v e n d u l a e (1981)

StreDtomvces r u b e l l o m u r i n e s (1981)

StreDtomvces Dlumbeus (1976)

Acanthamoeba c a s t e l l a n i i

StreDtomvces v i r i d o c h r o m o a e n e s

A. xantoarammica

A. xantoarammica

46

A n t h o D l e u r a xantoarammica

(1967)

45

5

Ref.

Zoanthus s o c i a t u s Tetrahvmena D v r i f o r m e s (1964)

rumen p r o t o z o a (1959)

Date and Source o f f i r s t isolation

T a b l e I. Date and Source o f F i r s t I s o l a t i o n o f V a r i o u s


HOAGLAND


Table I I . J_n v i t r o Enzyme I n h i b i t i o n by Various Aminophosphonates Enzyme name and EC number

Ref.

Adenylosuccinase (4.3.2.2)

'71

Carboxypeptidase A (3.4.2.1)

91, 92

Adenylosuccinase synthetase (6.3.4.4)

71

Carnosine synthetase (6.3.2.11)

93

Cholinesterase (3.1.1.8)

94

Chymotrypsin (3.4.21.1)

95

C y t i d i n e deaminase (3.5.4.5)

96


D-Ala-D-Ala synthetase " (6.3.2.4) A l a n i n e dehydrogenase (1.4.1.1) L-Alanine racemase (5.1.1.1)

72, 73, 74 71 75, 76 73

1Ref.

Enzyme name and EC number

A l k a l i n e phosphatase (3.1.3.1)

77

5-Dehydroquinate (4.6.1.3)

83

D-Amino a c i d t r a n s aminase (2.6.1.21)

78

3-Deoxy-D-arabinoheptulosonate-7phosphate synthase (4.1.2.15)

97

E l a s t a s e (3.4.21.11)

95

Angiotensis converting enzyme (3.4.15.1) A n t h r a n i l a t e synthase (4.1.3.27)

79, 80, 81, 82 83

Arginase (3.5.3.1)

71, 84

A r g i n i n e transamidinase (3.5.3.6)

71, 84

Asparagine synthetase (6.3.1.1)

85

Asparagine synthetase (glutamine h y d r o l y z i n g , 6.3.5.4)

86

Asparaginyl-t-RNA synthetase (6.1.1.12)

5-Enolpyruvylshikimate98 3-phosphate synthase 5phosphoshikimate-l-carboxyv i n y l - t r a n s f e r a s e (2.5.1.19) Ethanolamine phosphatecytidyl transferase (2.7.7.14)

99

Glutamine synthetase (6.3.1.2)

70, 87, 100 -104

-Glutamyl c y s t e i n e synthetase (6.3.2.2)

105

87

Isoleucyl-t-RNA synthetase (6.1.1.5)

106

Aspartase (4.3.1.1)

71

Leucine aminopeptidase (3.4.11.1, c y t o s o l i c )

107

A s p a r t a t e aminot r a n s f e r a s e (2.6.1.1)

71 Leucine aminopeptidase (3.4.11.2, mircosomal)

107

A s p a r t a t e carbamoyl t r a n s f e r a s e (2.1.3.2)

88-90

Methionyl-t-RNA synthetase 108, (6.1.1.10) 109, 110 O r n i t h i n e carbamoyl t r a n s f e r a s e (2.1.3.3)

Leucyl-t-RNA synthetase (6.1.1.4) Sphingosine 1-phosphate l y a s e (4.7.7.)

121

106

T y r o s i n a s e (1.10.3.1)

107

111-113 T y r o s i n e amino t r a n s f e r a s e 122 (2.6.1.5) 114

T y r o s i n e decarboxylase (4.1.1.25)

122

Phenylalanyl-t-RNA synthetase (6.1.1.b) Phospholipase C (3.1.4.3)

115

Tyrosyl-t-RNA synthetase (6.1.1.1)

122, 114

Pyruvate kinase (2.7.1.40)

116

UDP-NAMA-L-Ala synthetase (6.3.2.8)

72, 73

Rennin (3.4.4.15) S e r i n e transhydroxymethylase (2.1.2.1)

118-120

Valyl-t-RNA synthetase 106-110, (6.1.1.9) 114, 123-124

120


190


range o f enzyme systems, i t i s h i g h l y p r o b a b l e t h a t s p e c i f i c phosphonates can be found which w i l l i n h i b i t key p l a n t enzymes, making them p o s s i b l e h e r b i c i d e c a n d i d a t e s . Some phosphonate compounds can s e r v e as s u b s t r a t e s f o r s e v e r a l enzymes. Readers a r e r e f e r r e d t o a more comprehensive r e v i e w f o r f u r t h e r i n f o r m a t i o n on enzyme phosphonate i n t e r a c t i o n s ( 3 8 ) .


Phosphonates as H e r b i c i d e s , P l a n t Growth R e g u l a t o r s , Fungicides

and/or

T h e r e a r e many r e p o r t s i n the s c i e n t i f i c and p a t e n t l i t e r a t u r e d e s c r i b i n g phosphonates as h e r b i c i d e s , f u n g i c i d e s , and p l a n t growth regulators. T a b l e I I I i s a c o m p i l a t i o n o f some o f t h e s e compounds and shows t h e i r wide d i v e r s i t y o f c h e m i c a l s t r u c t u r e and b i o l o g i c a l activity. The most w i d e l y known and used o f the s y n t h e t i c phosphonates w i t h a g r i c u l t u r a l a p p l i c a t i o n s i s t h e h e r b i c i d e glyphosate, N-(phosphonomethyl)glycine, which was i n t r o d u c e d i n 1971 (124). T h i s compound combines h i g h , broad-spectrum h e r b i c i d a l a c t i v i t y w i t h low mammalian t o x i c i t y and a s h o r t h a l f - l i f e i n soils. The i n t e r e s t i n g l y p h o s a t e i s demonstrated by the voluminous r e p o r t s and p a t e n t s d e a l i n g w i t h i t s a p p l i c a t i o n and b i o c h e m i c a l and physiological action. A l s o , i t s u t i l i t y as a h e r b i c i d e g e n e r a t e d an enormous response i n the s y n t h e s i s o f a n a l o g s . Perhaps up t o a thousand g l y p h o s a t e d e r i v a t i v e s and a n a l o g s have been s y n t h e s i z e d and s c r e e n e d f o r h e r b i c i d a l a c t i v i t y (151). This stimulus of s y n t h e s i s produced some compounds w i t h h e r b i c i d a l a c t i v i t y , but none w i t h a c t i v i t y comparable t o g l y p h o s a t e . B i o c h e m i c a l and p h y s i o l o g i c a l s t u d i e s on t h e e f f e c t s o f g l y p h o s a t e have been examined by v a r i o u s w o r k e r s . F i g u r e 5 i n d i c a t e s some o f the major enzyme systems t e s t e d f o r i n v i t r o and i n v i v o e f f e c t s o f glyphosate. The mode o f a c t i o n o f g l y p h o s a t e i s c o n s i d e r e d t o be the i n h i b i t i o n of 5-enolpyruvylshikimate-3-phosphate synthase a c t i v i t y (168). There p r o b a b l y e x i s t n e a r l y 2,000 p u b l i c a t i o n s i n t h e s c i e n t i f i c l i t e r a t u r e on g l y p h o s a t e and i t s a c t i v i t y i n p l a n t s , s o i l s , and b a c t e r i a l systems. The r e a d e r i s r e f e r r e d t o r e v i e w s which c o v e r t h e many a s p e c t s o f the i m p o r t a n t r e s e a r c h conducted on t h i s h e r b i c i d e (169, 170, 171). G l y p h o s a t e i s not m e t a b o l i z e d a p p r e c i a b l y i n p l a n t s , but some microorganisms degrade i t r a p i d l y , and the major m e t a b o l i t e i s aminophosphonic a c i d . T h i s compound i s e s s e n t i a l l y n o n - t o x i c t o f i s h and w i l d l i f e . The next t h r e e most i m p o r t a n t compounds i n T a b l e I I I w i t h r e g a r d t o the p r e s e n t t o p i c a r e p h o s p h i n o t h r i c i n , b i a l a p h o s , and p h o s a l a c i n e which a r e n a t u r a l l y o c c u r r i n g s u b s t i t u t e d phosphonate compounds w i t h p o t e n t h e r b i c i d a l a c t i v i t y . B i a l a p h o s and p h o s a l a c i n e a r e p e p t i d e s c o n t a i n i n g a p h o s p h i n o t h r i c i n moiety. B i a l a p h o s has r e c e n t l y been marketed as a h e r b i c i d e i n Japan. This n a t u r a l l y o c c u r r i n g h e r b i c i d a l compound i s n o n - s e l e c t i v e and c o n t r o l s s e v e r a l s p e c i e s o f monocot and d i c o t weeds. I t has a h a l f - l i f e o f about 20-30 days i n s o i l and has low t o x i c i t y t o n o n - t a r g e t organisms (126). Hoechst AG i s d e v e l o p i n g c h e m i c a l l y s y n t h e s i z e d p h o s p h i n o t h r i c i n as the h e r b i c i d e HOE 39866, w i t h the common name g l u f o s i n a t e (125). In c o n t r a s t t o the many l i t e r a t u r e r e f e r e n c e s on g l y p h o s a t e , r e l a t i v e l y few r e p o r t s e x i s t on t h e b i o c h e m i c a l , p h y s i o l o g i c a l , and a p p l i e d a s p e c t s o f b i a l a p h o s , p h o s a l a c i n e , and p h o s p h i n o t h r i c i n . Most o f t h e s e d e a l w i t h the



2

3

2

3

2

3

2

2

2

2

2

2

2

2

3

2

2

CH -CH -0-P0 "-CO-NH

3

3

2

2

2

NH

4

+

fosamine ammonium

and o t h e r p e p t i d e s , contact herbicides

3

and N - g l y c y l d e r i v a t i v e

Ch -CH(NH )CONH-CH(CH )P0 H

3

R-C(P0 H ),NR'R"

2

R'=alky o r a c y l and R=alky o r a r y l (herbicide, defoliant)

post-emergence h e r b i c i d e

R=R'=H and R"=pyridyl herbicide

3

CH -CH(NH )-P(CH )0 H

2

R'-NH-C(R) -PO(OR)

2

(HOOC-CH -NH-CH ) P0 H

2

R-NH-CH -P0 H

3

CH -NH-CH -P0 H

172, 175

148

138-147

137

131-136

130

129

128

post-emergence h e r b i c i d e herbicide

127

phosalacine

2

phosphinothricin-ala-ala

2

phosphinothricin-ala-leu

2

69

125 126

3

glyphosate p h o s p h i n o t h r i c i n and g l u f o s i n a t e , (ammonium salt o f phosphinothricin) bialaphos

2

Reference

Activity

H00C-CH(NH )-CH2-CH -P(CH )0 H

2

HOOC-CH -NH-CH -P0 H

Herbicides:

Name o r Remarks

T a b l e I I I . Phosphonate Compounds with H e r b i c i d a l , F u n g i c i d a l , and P l a n t Growth R e g u l a t i n g



Table III.

Continued.


13. HOAGLAND


193

TANNINS


CHLOROGENIC

\

GALLIC ACID SINAPIC ACID FERULIC ACID

LIGNINS '

\ ISOFLAVONOIDS FLAVONOIDS CHALCONES

CAFFEIC ACID

ACID

i-CINNAMATE ®T

» £-COUMARATE » AMMONIA «

PROTEIN

TRYPTOPHAN

PHENYLALANINE

S®

Ν© PREPHENATE

—

—

—

t ®

CHORISM ATE t ® t © f ®

SHIKIMATE

© © 3-DEOXY-D-ARABINO-HEPTULOSONATE-7-P

© ERYTHROSE-4-Ρ·

PHOSPHOENOL PYRUVATE

F i g u r e 5. S c h e m a t i c o f v a r i o u s i n t e r m e d i a t e s a n d p r o d u c t s o f p h e n o l i c m e t a b o l i s m a n d some o f t h e e n z y m e s w h i c h h a v e b e e n examined f o r e f f e c t s o f g l y p h o s a t e . Enzymes: 1, 3 deoxy-2-oxo-D-arabinoheptulosate-7-phosphate s y n t h a s e ; 2, 5 - d e h y d r o q u i n a t e s y n t h a s e ; 3, s h i k i m a t e d e h y d r o g e n a s e ; 4, s h i k i m a t e k i n a s e ; 5, 5 - e n o l p y r u v y l s h i k i m a t e - 3 - p h o s p h a t e s y n t h a s e ; 6, c h o r i s m a t e s y n t h a s e ; 7, c h o r i s m a t e m u t a s e ; 8, prephenate d e h y d r o g e n a s e ; 9, t y r o s i n e a m i n o t r a n s f e r a s e ; 1 0 , p r e p h e n a t e dehydratase; 11, p h e n y l a l a n i n e a m i n o t r a n s f e r a s e ; 12, a n t h r a n i l a t e s y n t h a s e ; 13, t r y p t o p h a n s y n t h a s e ; 14, p h e n y l a l a n i n e ammonia-lyase; 15, t y r o s i n e ammonia-lyase; and 16, p o l y p h e n o l oxidase. Reproduced from R e f . 169. C o p y r i g h t 1982 A m e r i c a n C h e m i c a l S o c i e t y .



194


e f f e c t s o f p h o s p h i n o t h r i c i n on GS s i n c e t h e compound was i n i t i a l l y found t o be a s t r o n g GS i n h i b i t o r and because i t i s an a n a l o g o f a n o t h e r p o t e n t GS i n h i b i t o r , m e t h i o n i n e s u l f o x i m i n e . A b r i e f r e v i e w o f t h e b i o c h e m i c a l , p h y s i o l o g i c a l , and mode o f a c t i o n r e s e a r c h on t h e s e n a t u r a l l y o c c u r r i n g phosphonate h e r b i c i d e s w i l l be p r e s e n t e d i n a l a t e r s e c t i o n of t h i s chapter. Fosamine-ammonium, used p r i m a r l y f o r b r u s h c o n t r o l (172), i s t r a n s l o c a t e d i n both s u s c e p t i b l e and t o l e r a n t woody p l a n t s , b u t s u s c e p t i b l e p l a n t s a b s o r b and t r a n s l o c a t e s i g n i f i c a n t l y g r e a t e r q u a n t i t i e s o f t h e h e r b i c i d e t h a n do t o l e r a n t s p e c i e s . I t was proposed t h a t t h e p h y t o t o x i c i t y o f fosamine-ammonium i s due t o i t s a c t i o n o r t h e a c t i o n o f a m e t a b o l i t e a t o r above t h e p o i n t o f c o n t a c t (173). N e s q u i t e growth was i n h i b i t e d f o r up t o t h r e e y e a r s f o l l o w i n g t r e a t m e n t w i t h t h i s compound. These s t u d i e s i n d i c a t e t h e h e r b i c i d e i n h i b i t e s p r o t e i n and n u c l e i c a c i d s y n t h e s i s (174). Fosamine- ammonium i s r a p i d l y degraded by m i c r o o r g a n i s m s . The h a l f - l i f e i n s o i l i s about 10 days, compared t o about 2-3 weeks i n greenhouse-grown a p p l e s e e d l i n g s (175). Some phosphonates a r e used as commercial p l a n t growth regulators. Ethephon ( 2 - c h l o r o e t h y l p h o s p h o n i c a c i d ) i s used t o a c c e l e r a t e r i p e n i n g , i n d u c e f l o w e r i n g , promote a b s c i s s i o n , and t o s t i m u l a t e c o l o r (175). The a c t i o n o f t h i s compound i s v i a p r o d u c t i o n o f e t h y l e n e , a p r o d u c t o f ethephon d e g r a d a t i o n . The glyphosate analog, glyphosine [N,N,-bis(phosphonomethyl)glycine] i s used c o m m e r c i a l l y as a suger cane r i p e n e r . A t h i g h l e v e l s i t shows some h e r b i c i d a l a c t i v i t y and causes growth c e s s a t i o n , c h l o r o s i s , and d e s i c a t i o n (155). T h i s compound c a n reduce numbers o f 70-S ribosomes and c h l o r o p l a s t i c r i b o s o m a l RNA, b u t has no e f f e c t on p h o t o p h o s p h o r y l a t i o n (152). Other phosphonate p l a n t growth r e g u l a t o r s a r e p r o p y l p h o s p h o n i c a c i d , e t h y l h y d r o g e n p r o p y l p h o s p h o n a t e , and NIA 10637 (176). Ethyl p r o p y l p h o s p h o n a t e r e t a r d s t h e growth o f v a r i o u s woody s p e c i e s , and causes p h y s i c a l r e s p o n s e s such as i n c r e a s e d c o l d h a r d i n e s s , seed g e r m i n a t i o n i n d u c t i o n , and a f f e c t s f l o w e r i n g and f r u i t i n g . Several o t h e r a r o m a t i c phosphonates a r e r e p o r t e d t o have p l a n t growth regulator a c t i v i t y . S e v e r a l phosphonates have p o t e n t i a l as fungicides. V a r i o u s organophosphonates (some o f t h e organophosphonate c l a s s ) have been d e v e l o p e d over t h e p a s t 15 y e a r s which have r e l a t i v e l y low mammalian t o x i c i t y and e n v i r o n m e n t a l p e r s i s t a n c e compared t o t h e o r g a n o c h l o r i n e i n s e c t i c i d e s (177). Some o f t h e s e compounds a r e p r e s e n t e d and d i s c u s s e d elsewhere (178). There a r e a p p a r e n t l y no r e p o r t s o f n a t u r a l l y o c c u r r i n g phosphonates with useful i n s e c t i c i d a l a c t i v i t y . P h o s p h i n o t h r i c i n , B i a l a p h o s , and P h o s a l a c i n e as H e r b i c i d e s D i r c o v e r y and E a r l y Development. P h o s p h i n o t h r i c i n was i s o l a t e d from c u l t u r e s o f Streptomyces v i r i d o c h r o m o g e n e s (47) and from S. h y g r o s c o p i c u s as t h e p h o s p h i n o t h r i c y l a l a n y l a l a n i n e p e p t i d e (now c a l l e d b i a l a p h o s ) (179). T h i s t r i p e p t i d e was shown t o be a c t i v e as a b a c t e r i c i d e a g a i n s t Gram-negative and G r a m - p o s i t i v e b a c t e r i a and as a f u n g i c i d e a g a i n s t t h e f u n g i B o t r y t i s c i n e r e a , R h l z o c t o n i a s o l a n i , and P i r i c u l a r i a o r y z a e (180). The h e r b i c i d a l a c t i v i t y o f b i a l a p h o s was d e s c r i b e d i n 1979 (181). P h o s p h i n o t h r i c i n was f i r s t s y n t h e s i z e d i n 1972 ( 4 7 ) , and d e t a i l s and d i s c u s s i o n o f i t s



13. HOAGLAND


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s y n t h e s i s a r e p r e s e n t e d elsewhere (104). Herbicidal properties of p h o s p h i n o t h r i c i n as a c o m m e r i c a l l y s y n t h e s i z e d ammonium s a l t were f i r s t r e p o r t e d i n 1977 (182). P h o s a l a c i n e i s a phosphonate p e p t i d e analog of bialaphos d i f f e r i n g only i n that i t possesses a C-terminal l e u c i n e r e s i d u e i n s t e a d o f a l a n i n e . T h i s compound was r e p o r t e d t o be a h e r b i c i d a l i s o l a t e from K i t a s a t o s p o r i a p h o s a l a c i n e a , an A c t i n o m y c e t e from s o i l (183). Streptomyces and A c t i n o m y c e s b e l o n g t o s e p a r a t e f a m i l i e s w i t h i n t h e same o r d e r ( A c t i n o m y c e t a l e s ) and produce v e r y s i m i l a r phosphonate p e p t i d e s . More r e c e n t l y , p h o s a l a c i n e has been p a t e n t e d as a d e f o l i a n t f o r hops (Humulus l u p u l u s ) (184). G e n e r a l P r o p e r t i e s and H e r b i c i d a l A c t i v i t y . B i a l a p h o s i s a c t i v e on t h e f o l i a g e o f v a r i o u s weeds, i n c l u d i n g p e r e n n i a l s (185). I t s p h y t o t o x i c i t y i s e x p r e s s e d more s l o w l y than t h a t o f p a r a q u a t , b u t more r a p i d l y t h a t t h a t o f g l y p h o s a t e . When f i v e weeds w i t h an LD range o f Q ) . R e d r a w n w i t h p e r m i s s i o n f r o m R e f . 1 8 3 . C o p y r i g h t 1984 J a p a n e s e A n t i b i o t i c s Research Association.


13. HOAGLAND


197


P h o s p h i n o t h r i c i n can a l s o i n c r e a s e e x t r a c t a b l e PAL a c t i v i t y on a f r e s h weight and a s p e c i f i c a c t i v i t y b a s i s i n soybean t i s s u e s (Hoagland, u n p u b l i s h e d d a t a ) . These e f f e c t s on g l y p h o s a t e , g l u f o s i n a t e , and p h o s p i n o t h r i c i n a r e c o n s i d e r e d t o be o n l y secondary w i t h r e g a r d t o i t s mode o f a c t i o n which i n v o l v e s GS i n h i b i t i o n , as d i s c u s s e d below. I n h i b i t i o n o f GS by N a t u r a l l y O c c u r r i n g Phosphonates. I t has been known s i n c e 1959 t h a t some phosphonic and p h o s p h i n i c a c i d a n a l o g s o f g l u t a m i c a c i d were i n h i b i t o r y t o g l u t a m i n e s y n t h e t a s e ( 7 0 ) . S i n c e then, v a r i o u s o t h e r P-C c o n t a i n i n g a n a l o g s have been s y n t h e s i z e d and some a l s o i n h i b i t t h i s enzyme from mammalian (191-193) and p l a n t s o u r c e s (101, 104, 191, 194). P h o s p h i n o t h r i c i n was r e p o r t e d as an i n h i b i t o r o f GS as e a r l y as 1972 ( 4 7 ) . There a r e a l s o known n a t u r a l l y o c c u r r i n g compounds o t h e r than t h o s e c o n t a i n i n g C-P bonds t h a t e x h i b i t p o t e n t i n h i b i t i o n o f GS a c t i v i t y . Comparative s t r u c t u r e s o f t h e s e n a t u r a l p r o d u c t s and s u b s t i t u t e d phosphonate a n a l o g s t h a t a r e GS i n h i b i t o r s a r e g i v e n i n F i g u r e 7. Oxetin, d e r i v e d from Streptomyces s p . , i s a r e c e n t l y d i s c o v e r e d GS i n h i b i t o r (195). T a b t o x i n i n e - p - l a c t a m , a l s o an i n h i b i t o r o f GS (196), i s produced by Pseudomonas t a b a c i (197). The GS i n h i b i t o r L-methionine s u l f o x i m i n e (198) i s found i n t h e bark o f a t r e e , C n e s t i s g l a b r a (199), but t h e i n h i b i t o r y a c t i o n o f s y n t h e s i z e d m e t h i o n i n e s u l f o x i m i n e has been known and u t i l i z e d f o r y e a r s ( 2 0 ) ) . L-(N -phosphono)methionine-S-sulfoximine i a metabolite of the N-phosphono compound, L-(N -phosphono)methionine-S-sulfoximinyl-La l a n y l - L - a l a n i n e (200), a n o t h e r Streptomyces p r o d u c t (201). This l a t t e r compound s h o u l d , however, n o t be c o n f u s e d w i t h carbon-phosphono compounds and t h e d i f f e r e n c e i s a p p a r e n t when s t r u c t u r e s a r e compared. G l y p h o s a t e d i d n o t i n h i b i t GS a c t i v i t y i n an enzyme p r e p a r a t i o n from pea (Pisum s a t i v u m L.) (104). P h o s p h i n o t h r i c i n was found t o be a more p o t e n t i n h i b i t o r o f GS from bean (Phaseolus v u l g a r i s L.) pod t i s s u e and o v i n e b r a i n t h a n m e t h i o n i n e s u l f o x i m e (202), w h i l e g l y p h o s a t e and 2-amino-4-phosphonobutyric a c i d a t c o n c e n t r t i o n s o f up t o 1 mM had no i n h i b i t o r y a c t i v i t y . e

s

e

Glutamine s y n t h e t a s e i n p l a n t s i s t h e key enzyme o f t h e GS/G0GAT (glutamine synthetase/glutamine:2-oxoglutarate aminotransferase) pathway and p l a y s a c r u c i a l r o l e i n t h e a s s i m i l a t i o n / r e a s s i m i l a t i o n o f ammonia (203, 204). A n a l y s i s o f two GS isozymes from v a r i o u s p l a n t s p e c i e s show a wide range o f r a t i o s f o r t h e isozymes w i t h s i m i l a r K± v a l u e s f o r p h o s p h i n o t h r i c i n , but no c o r r e l a t i o n w i t h whole p l a n t s u s c e p t i b i l i t y t o p h o s p h i n o t h r i c i n (186). T h i s suggests t h a t whole p l a n t s u s c e p t i b i l i t y i s not r e l a t e d t o d i f f e r e n c e s i n t h e degree o f enzyme i n h i b i t i o n . GS Isozymes from wheat r o o t s and l e a v e s i s s t r o n g l y i n h i b i t e d by p h o s p h i n o t h r i c i n i n v i t r o , however, t h e r o o t enzyme was more s t r o n g l y i n h i b i t e d by t h e h e r b i c i d e than was t h e c h l o r o p l a s t enzyme (194). The k i n e t i c s o f i n h i b i t i o n o f GS from pea l e a v e s by p h o s p h i n o t h r i c i n and m e t h i o n i n e s u l f o x i m i n e i n d i c a t e d an apparent K o f 0.073 mM and 0.16 mM, r e s p e c t i v e l y (205) . P h o s p h i n o t h r i c i n a l s o i n h i b i t s GS i n b a c t e r i a (47) and a l g a e (206) . K i n e t i c s t u d i e s have shown t h a t t h e n a t u r e o f p h o s p h i n o t h r i c i n i n h i b i t i o n o f GS a c t i v i t y i s i r r e v e r s i b l e and c o m p e t i t i v e with r e s p e c t t o glutamate. ±




0 II CH-P 3

I OH

-CH-CH-CH-CO-NH-CH-CO-NH-CH-COOH I I I NH CH CH 2

2

2

3

o

3

Bialaphos 0 II CH-P -CH-CH-CH-COOH I I OH NH Phosphinothricin 3

2

2

2

0 II CH-S-CH-CH-CH-COOH 3„

2

2,

NH NH Methionine sulfoximine 2

Ο II CH-S-CH-CH-CH-COOH II 2 2, N-PO H NH 3

o

3 2

2

L- (N-phosphono)-methionine-S-sulfoximine Ο II HN-C I I HC-C-CH-CH-CH-COOH 2

ι

2

2 ,

OH NH Tabtoxinine-/3-lactam 2

0-CH-COOH I I HC-CH-NH 2 2 Oxetin F i g u r e 7. S t r u c t u r e s o f s e v e r a l n a t u r a l l y o c c u r r i n g compounds w i t h p o t e n t i n v i t r o i n h i b i t i o n o f GS a c t i v i t y .



13. HOAGLAND


199

Glutamine Antagonism and Ammonia T o x i c i t y . B i a l a p h o s a t c o n c e n t r a t i o n s up t o 3 mM d i d n o t i n h i b i t GS a c t i v i t y i n p l a n t s o f Japanese b a r n y a r d m i l l e t ( E c h i n o c h l o a u t i l i s ) but lowered e x t r a c t a b l e a c t i v i t y i n t r e a t e d s h o o t s (207). Phosphinothricin i n h i b i t e d GS b o t h i n v i t r o and e x t r a c t a b l e a c t i v i t y o f t r e a t e d shoots o f t h i s s p e c i e s . G l u t a m i n e c o n t e n t was r e d u c e d i n b i a l a p h o s - t r e a t e d s h o o t s 48 hours a f t e r t r e a t m e n t , but exogenous g l u t a m i n e d i d n o t a m e l e o r a t e b i a l a p h o s p h y t o t o x i c i t y . Glutamine has been r e p o r t e d t o a n t a g o n i z e b i a l a p h o s - c a u s e d growth i n h i b i t i o n on B a c i l l u s s u b t i l i s and C a m e l l i a j a p o n i c a L. p o l l e n t u b e s (47, 208) and t h e i n h i b i t i o n o f GS i n E. c o l i by p h o s p h i n o t h r i c i n (47). This p r o t e c t i v e e f f e c t o f g l u t a m i n e has a l s o been demonstrated i n o t h e r p l a n t s p e c i e s (209). Ammonia has been shown t o accumulate t o t o x i c l e v e l s i n plants treated with bialaphos or phosphinothricin (210-214). T h i s was n o t t o t a l l y unexpected s i n c e ammonia i n c r e a s e s i n p l a n t s t r e a t e d w i t h o t h e r GS i n h i b i t o r s , such as m e t h i o n i n e s u l f o x i m i n e (215), and t a b t o x i n (216). S i t e ( s ) o f A c t i o n o f P h o s p h i n o t h r i c i n . I n h i b i t i o n o f GS by phosphinothricin r e s u l t e d i n s u b s t a n t i a l light-dependent a c c u m u l a t i o n o f ammonia, i n h i b i t i o n o f p h o t o s y n t h e s i s , and e v e n t u a l p l a n t d e a t h (214). Because ammonia can o c c u r from t h r e e major s o u r c e s i n t h e p l a n t : (1) i n o r g a n i c n i t r o g e n a s s i m i l a t i o n , (2) c a t a b o l i c o r a n a b o l i c p r o c e s s e s , and (3) p h o t o r e s p i r a t i o n , t h e s e r e s e a r c h e r s a l s o examined t h e i n f l u e n c e o f n i t r a t e a s s i m i l a t i o n and p h o t o r e s p i r a t i o n as causes f o r ammonia a c c u m u l a t i o n i n p l a n t s treated with phosphinothricin. P h o t o r e s p i r a t i o n was r e s p o n s i b l e f o r about 60% o f t h e ammonia formed. S i n c e n i t r a t e r e d u c t i o n was found t o have a n e g l i g i b l e i n f l u e n c e on i n h i b i t i o n o f p h o t o s y n t h e s i s a t an e a r l y s t a g e , about 40% o f t h e i n c r e a s e d ammonia was s u g g e s t e d t o o r i g i n a t e from c a t a b o l i c o r a n a b o l i c r o u t e s . C o r r e l a t i o n s between ammonia c o n c e n t r a t i o n and p h o t o s y n t h e s i s l e v e l s were s i m i l a r r e g a r d l e s s o f n i t r a t e a d d i t i o n , and C 0 f i x a t i o n under non-photorespiratory c o n d i t i o n s remains l a r g e l y i n t a c t even a t h i g h ammonia l e v e l s . C o n t r a r y t o t h i s , n i t r o g e n f e r t i l i z e r s have been r e p o r t e d t o enhance b i a l a p h o s e f f i c a c y , p o s s i b l y due t o i n c r e a s i n g ammonia l e v e l s (217). However, t h e h e r b i c i d e g l u f o s i n a t e lowered n i t r a t e r e d u c t a s e l e v e l s i n r o o t s o f l i g h t - g r o w n soybeans (218). a

To c l a r i f y t h e r e l a t i o n s h i p o f p h o s p h i o t h r i c i n i n h i b i t i o n o f GS w i t h t h e r e d u c t i o n o f C 0 f i x a t i o n and t o e v a l u a t e t h e r o l e o f g l u t a m i n e , s t u d i e s were c o n d u c t e d on p r o t o p l a s t s , c h l o r o p l a s t s , and whole l e a v e s (209). R e s u l t s suggested that glutamine d e p l e t i o n caused by p h o s p h i n o t h r i c i n i s t h e main cause o f e a r l y p h o t o s y n t h e s i s i n h i b i t i o n and t h r e e s e n a r i o s which may be o p e r a t i v e i n t h e i n h i b i t i o n o f p h o t o s y n t h e s i s were p r o p o s e d ( F i g u r e 8 ) . B a s i c a l l y t h e s e i n v o l v e (1) i n h i b i t i o n o f p r o t e i n b i o s y n t h e s i s ; a l a c k o f r e g e n e r a t i o n o f Q p r o t e i n i n v o l v e d i n l i g h t dependent e l e c t r o n t r a n s p o r t would l e a d t o b l o c k a g e o f p h o t o s y n t h e t i c e l e c t r o n t r a n s p o r t ; an amino donor would not be p r e s e n t even f o r g l y o x y l a t e t r a n s a m i n a t i o n ; (2) t o x i c g l y o x y l a t e a c c u m u l a t i o n ; g l y o x y l a t e i s an i n h i b i t o r o f RuDP c a r b o x y l a s e / o x y g e n a s e (219), and (3) C a l v i n c y c l e i n t e r m e d i a t e d e p l e t i o n ; l a c k o f GS ( o r o t h e r enzymes t h a t p r e v e n t c a r b o n f l o w i n t o p h o t o r e s p i r a t i o n by t h e oxygenase r e a c t i o n ) l e a d s t o a l a c k o f RuDP f o r t h e C a l v i n c y c l e . a

B



200


Glu

ΗΝ 3

j G , n

• toxic NH accumulation 4

^^^transamidation

•nucleotide depletion inhibition of protein synthesis

transamination—•toxic accumulation of glyoxylate depletion of Calvin cycle intermediates F i g u r e 8. P o s s i b l e s i t e s o f p h o s p h i n o t h r i c i n mode o f a c t i o n . Redrawn w i t h p e r m i s s i o n f r o m R e f . 209. C o p y r i g h t 1987 V e r l a g d e r Z e i t s c h r i f t f u r Naturforschung.


13.

HOAGLAND


B i o t e c h n o l o g l c a l and B i o c h e m i c a l A s p e c t s o f B i a l a p h o s P r o d u c t i o n . The pathway f o r t h e b i o s y n t h e s i s o f b i a l a p h o s has been d e t e r m i n e d u t i l i z i n g C - l a b e l e d p r e c u r s o r s , b l o c k e d mutants, m e t a b o l i c i n h i b i t o r s , and a n a l y s i s o f p r o d u c t s accumulated and c o n v e r t e d by a s e r i e s o f n o n - p r o d u c i n g mutants o f S. h y g r o s c o p i c u s ( F i g u r e 9 ) . V e r y r e c e n t l y , e x p e r i m e n t a t i o n has r e s u l t e d i n t h e i s o l a t i o n and m a n i p u l a t i o n o f genes r e s p o n s i b l e f o r b i a l a p h o s b i o s y n t h e s i s i n S. h y g r o s c o p i c u s (220). U s i n g a p l a s m i d v e c t o r , p r o d u c t i o n genes f o r t h i s h e r b i c i d e were c l o n e d from genomic DNA. S e v e r a l p l a s m i d s were i s o l a t e d which r e s t o r e d b i a l a p h o s p r o d u c t i v i t y t o mutants o f S. h y g r o s c o p i c u s ) t h a t were b l o c k e d a t d i f f e r e n t p o i n t s i n t h e b i o s y n t h e t i c pathway. A gene c o n f e r r i n g r e s i s t a n c e t o b i a l a p h o s was a l s o l i n k e d t o t h e p r o d u c t i o n genes. Mapping d e f i n e d t h e l o c a t i o n of t h e s e genes i n a 16 k d c l u s t e r . How t h e s e genes a r e c o n t r o l l e d ; i . e . , t h e t r a n s c r i p t i o n a l o r g a n i z a t i o n o f t h e c l u s t e r and t h e i n v o l v e m e n t o f r e g u l a t o r y genes remains t o be d e t e r m i n e d .


x a

Stereochemical Considerations. Absolute c o n f i g u r a t i o n of a b i a l a p h o s i n t e r m e d i a t e , 2-phosphinomethylmalic a c i d , has r e c e n t l y been found i n t h e S c o n f i g u r a t i o n (221). T h i s f a c t i s important i n the d e t e r m i n a t i o n o f t h e mechanism o f t r a n s f o r m a t i o n o f t h i s compound t o d i m e t h y l p h o s p h i n o t h r i c i n and t h e enzymes r e s p o n s i b l e f o r those metabolic s t e p s . The o p t i c a l r e s o l u t i o n o f r a c e m i c p h o s p h i n o t h r i c i n has been r e p o r t e d (222) and i t was c o n f i r m e d t h a t t h e L form p o s s e s s e s h i g h h e r b i d i c a l a c t i v i t y whereas t h e D - p h o s p h i n o t h r i c i n had o n l y v e r y low phytotoxicity. Potential

o f N a t u r a l l y O c c u r r i n g Phosphonates as H e r b i c i d e s

One o f t h e new s t r a t e g i e s o f h e r b i c i d e d i s c o v e r y i s t h e development of h e r b i c i d e c h e m i c a l c l a s s e s based on p r o d u c t s t h a t o c c u r naturally. Only a s m a l l p e r c e n t a g e o f h i g h e r p l a n t s p e c i e s and microorganisms have been e x t e n s i v e l y examined f o r such compounds. Only a few n a t u r a l p r o d u c t s have been a d e q u a t e l y examined f o r p o t e n t i a l h e r b i c i d a l a c t i v i t y (223). Naturally occurring phosphonate compounds a r e p r e s e n t i n a v a r i e t y o f s p e c i e s and a r e p r o b a b l y i n many o t h e r s y e t u n t e s t e d . Furthermore, some o f t h e s e phosphonates t h a t have been i s o l a t e d and i d e n t i f i e d and t h o s e t h a t have been s y n t h e s i z e d have been shown t o c o n t a i n p o t e n t b i o l o g i c a l a c t i v i t y , i n c l u d i n g h e r b i c i d a l and p l a n t growth r e g u l a t i n g properties. B i a l a p h o s i s t h e f i r s t h e r b i c i d e (and t h e f i r s t n a t u r a l l y o c c u r r i n g phosphonate compound) produced by f e r m e n t a t i o n t e c h n o l o g y to a c h i e v e commerical s t a t u s . The a c t i v e component o f t h i s compound, p h o s p h i n o t h r i c i n , i s o f such c h e m i s t r y t h a t i t s s y n t h e s i s was e c o n o m i c a l l y f e a s i b l e and i t c o u l d be produced as t h e h e r b i c i d e g l u f o s i n a t e and marketed on a competetive b a s i s w i t h o t h e r s y n t h e t i c herbicides. Phosphonate compounds a r e now known t o be w i d e l y d i s t r i b u t e d i n n a t u r e and t h e s e compounds may e x i s t i n many l i v i n g systems y e t untested. T h i s , c o u p l e d w i t h t h e a c t i v i t y o f v a r i o u s s y n t h e t i c and n a t u r a l l y o c c u r r i n g phosphonates as enzyme i n h i b i t o r s and t h e s u c c e s s o f p h o s p h i n o t h r i c i n , b i a l a p h o s , and p h o s a l a c i n e as h e r b i c i d e s s u g g e s t s t h a t i n c r e a s e d s c r e e n i n g programs c o u p l e d w i t h


201


CH

2

2

I

2

I CH-NH

CH

2

2

2

2

2

3

—

2

2

2

2

N - A c e t y l DMPT

COOH

CH-NH-Ac

CH

I

CH

2

2

P0 H

PnAA

T~ C=0 co HI

CH

I n

—

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CHpOH

I

3

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H

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CO-AlaAla

I

2

2

2

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2

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2

P0 H CH

3

COOH

I

P0

2

—

PMM

CO-AlaAla

I

2

2

2

I CH I CH-NH-Ac

CH

2

CH COOH

I

2

HO-C-COOH

CH

2

N-Acetyl bialaphos

3

2

H C-P0 H

PPA

COOH

I

2

C=0

CH

2

Acetyl-CoA P0 H P0 H

F i g u r e 9. B i o s y n t h e t i c pathway o f b i a l a p h o s i n Streptomyces hygroscopicus. PEP=phosphoenolpyruvate; PnPy=phosphonopyruvate; PnAA=phosphonoacetaldehyde; HMP^hydroxymethylphosphonate; PF=phosphonoformate; PPA^phosphinopyruvate; PMM=phosphinomethylmalate; DKDPT=deamino-a-keto-demethylphosphinothricin; DMPT--=demethy L p h o s p h l n o t h r i c i n ; D M B A = d e m e t h y l b i a l a p h o s ; AlaAla=alanylalanine. Redrawn w i t h p e r m i s s i o n from R e f . 220. C o p y r i g h t 1986 S p r i n g e r V e r l a g .

DMPT

I

I

I

CH

2

PnPy

COOH

P0 H

2

2

3

C=0

I

CH

DKDPT

—

2

COOH

2

H

I

P0 H

COOH

I

I CHp I C=0

CH

2

P0 H

PEP

COOH

II C-O-PCU I

P0 H

2

9

bialaphos

CO-AlaAla

I

2

2

I CH I CH-NH

CH

2

COOH

H C-P0 H 3

2

CHOH

I I

CH H-C-COOH


j§ § cl

^ 3 ^ g £

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C

W

S C g§ Ρ

ο

13. HOAGLAND

203 Carbon-Phosphorus Compounds as Herbicides


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