Metabolism and Physiological Effects of the Pentoses and Uronic Acids

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Metabolism and Physiological Effects of the Pentoses and Uronic Acids OSCAR TOUSTER Department of Molecular Biology, Vanderbilt University, Nashville, Tenn. 37235

I. Introduction The importance of the pentoses needs little comment, since they are so well known to be components of DNA, RNA, coenzymes, ATP, and proteoglycans. Moreover, pentose phosphates are impor tant metabolic intermediates in such processes as CO fixation in photosynthesis. Similarly, uronic acids are components of proteo glycans, or mucopolysaccharides, and of metabolic pathways, including those leading to the pentoses. These structural and metabolic aspects will be briefly reviewed, as well as the utili zation of these substances and relevant pathological considera tions. 2

II.

The Physiologically Important Pentoses

Table I lists pentoses which are important in mammalian metabolism. TABLE I. PHYSIOLOGICALLY-IMPORTANT PENTOSES D-Ribose - in nucleotides, pentose phosphate pathway D-2-Deoxyribose - in deoxyribonucleotides D-Ribulose - in pentose phosphate pathway; Ru-1,5-DP is CO accep tor in photosynthesis 2

D-Xylulose - in pentose phosphate pathway, in glucuronic acidxylulose cycle L-Xylulose - in glucuronic acid-xylulose cycle, excreted in gram quantities by humans with essential pentosuria D-Xylose - in gal-gal-xyl linkage of mucopolysaccharide to protein 135 In Physiological Effects of Food Carbohydrates; Jeanes, Allene, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.

136

PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES

D-Ribose of course is a key component of RNA and other r i b o n u c l e o t i d e s , and D-ribose 5-phosphate is a member of the pentose phosphate pathway of carbohydrate metabolism. D-2-Deoxyribose is a component of the n u c l e o t i d e s in DNA. D-Ribulose, as the 5phosphate, i s an intermediate in the pentose phosphate pathway and, as the 1,5-diphosphate, i s the CO acceptor in photosynthesis. D-Xylulose as the 5-phosphate d e r i v a t i v e is an intermediate i n the pentose phosphate pathway and occurs as the f r e e sugar in the g l u c u r o n a t e - x y l u l o s e c y c l e , as described in the preceding paper i n t h i s symposium. L - X y l u l o s e is a l s o a member of the c y c l e and is noteworthy because of its rather l a r g e e x c r e t i o n by humans with the genetic metabolic d i s o r d e r known as e s s e n t i a l p e n t o s u r i a . In proteoglycans (mucopolysaccharides) D-xylose is the sugar r e s i d u e attached to s e r i n e i n the bridge l i n k i n g the polymeric carbohydrate to the p r o t e i n core. The s t r u c t u r e of the g a l a c t o s e - g a l a c t o s e - x y l o s e bridge was mainly worked out through the work of Lennart Rodén (1). Of course many other pentoses occur i n nature and a r e ingested in f o o d s t u f f s , but those l i s t e d i n Table I are of the g r e a t e s t importance to mammals in t h e i r normal metabolism.


2

III.

U t i l i z a t i o n of Pentoses

14 Table I I summarizes some experiments i n which C-labeled pentoses were administered to animals and man and t h e i r u t i l i z a t i o n estimated. Examination of the l i v e r glycogen column shows that r i b o s e i s u t i l i z e d as e f f e c t i v e l y as glucose. I t should be borne i n mind, however, that s i n c e these a r e t r a c e r q u a n t i t i e s of pentose, i t need not be t r u e that equivalent but l a r g e amounts of pentose would be u t i l i z e d as w e l l as glucose. In man D-xylose, D-ribose and D-lyxose are o x i d i z e d t o C0 to a moderate extent, a f i n d i n g c o n s i s t e n t with the f a c t that most of the l a b e l which appears i n the u r i n e occurs i n a form that i s not the administered sugar. In these experiments the sugars were infused i n human subjects over a 15-minute p e r i o d . The C 0 and l i v e r g l y c o gen experiments i n d i c a t e that L-arabinose i s u t i l i z e d only to a n e g l i g i b l e extent. Although D-xylose may be isomerized to D-xylulose by plant and b a c t e r i a l enzymes, i n mammals t h i s aldopentose i s e i t h e r reduced to x y l i t o l , an intermediate i n the g l u c u r o n a t e - x y l u l o s e c y c l e (7), or o x i d i z e d to f^-xylonic a c i d by an NAD-linked Dxylose dehydrogenase detected i n c a l f lens by Van Heyningen (8). fJ-Ribose i s converted to r i b o s e 5-phosphate, an intermediate i n the pentose phosphate pathway. The route of u t i l i z a t i o n of D-lyxose has not been e s t a b l i s h e d ; perhaps i t i s isomerized to D-xylulose. 2

2

In Physiological Effects of Food Carbohydrates; Jeanes, Allene, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1975.


Mouse Man Rat

Mouse Man Guinea p i g

Mouse Man

Mouse Man

Man

JL-Ribose

2-Xylose

D-Arabinose

L.-Arabinose

D-Lyxose

(Table adapted

-

-

-

-0.8 14

19

35 75

72

85

57

6-24

-

-

3 6-24

3 24 0

-

0.03

-

1.0

3 6-24 24

7.1

3 6-24 2

10.0

10

Time (Hrs.)

3

glycogen

8.3

Liver

-

16 15

In u r i n e

-

2

48 --

Oxid. to C 0

% of Administered Tracer Dose

UTILIZATION OF FREE PENTOSES BY MAMMALS

from Hollmann and Reinauer (6))

H i a t t (2) Segal and F o l e y (3) McCormick and Touster (4) McCormick and Touster (5)

Mouse

D-Glucose

a b c d

Species

Pentitose

TABLE I I .


b

a b

a b

a b d

a b c

a

Ref

138

IV.

PHYSIOLOGICAL

EFFECTS

Pentoses and D-Glucuronic A c i d as Metabolic

OF

FOOD

CARBOHYDRATES

Intermediates

The pentose phosphate pathway f o r glucose u t i l i z a t i o n i s shown i n F i g u r e 1. The main feature of t h i s pathway f o r glucose o x i d a t i o n i s that 3 molecules of glucose phosphate are o x i d i z e d , i n NADP-linked steps, to form 3 molecules of pentose phosphate. A s e r i e s of i s o m e r i z a t i o n s and group t r a n s f e r s occur which have the o v e r a l l e f f e c t of converting 3 molecules of hexose to 3 molec u l e s of f r u c t o s e phosphate and 1 molecule of glyceraldehyde phosphate plus 3 molecules of C0 . T h i s i s t h e r e f o r e the oxid a t i o n pathway of glucose metabolism. I t i s the main pathway f o r the production of NADPH, which i s the n u c l e o t i d e coenzyme commonly used i n r e d u c t i v e b i o s y n t h e t i c processes, and i t i s the route by which r i b o s e i s made f o r the production of n u c l e o t i d e s and f o r deoxyribose production as w e l l . I t should be emphasized that most of the r e a c t i o n s , although not the decarboxylations, are r e v e r s i b l e . Most of the r i b o s e 5-phosphate appears to be derived from t h i s pathway reading from r i g h t to l e f t , rather than l e f t to r i g h t , i n other words, from the non-oxidative p o r t i o n of the pathway. The phosphorylation of r i b u l o s e 5-phosphate to r i b u l o s e 1,5-diphosphate provides the C0 acceptor i n p l a n t s . We would a l s o point out that a l l pentoses i n t h i s pathway are phosphorylated. From the q u a n t i t a t i v e point of view, t h i s i s a minor pathway f o r carbohydrate o x i d a t i o n , i n comparison to the EmbdenMeyerhof g l y c o l y t i c route, but a greater amount of glucose i s d i r e c t e d through t h i s pathway when there i s need f o r NADPH. Another route by which pentoses are formed i s through the conversion of D-glucuronic a c i d to the x y l u l o s e s i n the g l u c u r o n i c - x y l u l o s e pathway,in which the pentose intermediates are not phosphorylated. A pentosuric i n d i v i d u a l excretes a rather constant amount of ^ - x y l u l o s e . The feeding of D-glucuronolactone elevates the u r i n a r y L - x y l u l o s e i n an amount i n d i c a t i n g that the conversion occurs i n rather high y i e l d (9). That t h i s i s a d i r e c t conversion has been demonstrated with l a b e l e d l a c t o n e . I t i s r e l e v a n t to mention that ^-glucuronate i s poorly converted to L - x y l u l o s e i n an experiment of t h i s type because, u n l i k e the lactone, the f r e e a c i d or s a l t i s poorly absorbed or impermeable to c e l l s .


2

2


Pentoses and

TOUSTER

Uronic Acids

Λ u sa

QOX O-O-O X X

*2 χ κ χ ο ο ; X X


Ί5Ε. S - - Ο Χ Χ Ν X*u χ ο ό Χ ν>ο-υ-ο-ο-ο

" 3

- Χ Χ ο ο ο XXX

"Ν

ο

s i

μ

11

χ

7Γε 11

« Λ

J( -a ; ν

Χ Ο

•Ο ι

ο ο χ

χ

ο Χ Χ Χ Ν χ •χ ο ο ο χ υ-ο-ο-ο-ο-ο-ϋ ο χ χ χ χ ATP i r

CH OH HCOH

CH OH HOCH

2

2

tL)

HOCH H-D-mannona t e

>-2-keto-3-deoxygluconate (KDG)

*KDG 6-phosphate

^-pyruvate + t r i o s e phosphate Plants

^ g l u c u r o n i c a c i d 1-P D-Glucuronate

UTp

'>UDPGlcUA •pectins and h e m i c e l l u l o s e s

-glucaric acid Animals ^ x y l u l o s e pathway ^*L-gulonate ^ ΓΙ-Glucuronate -^L-ascorbic a c i d ^ ^ - g l u c a r i c acid


8.

Pentoses and Uronic Acids

TOUSTER

145

TABLE I I I . PHYSIOLOGICALLY IMPORTANT URONIC ACIDS


CHO I HCOH I HOCH I HCOH I HCOH I COOH

D-Glucuronic a c i d - i n h e p a r i n , h y a l u r o n i c a c i d , c h o n d r o i t i n s u l f a t e s , e t c . , and glucuronides (of drugs and hor mones) ; i n v o l v e d i n metabolism of i n o s i t o l , L-ascorbic a c i d , and the x y l u l o s e s

CHO I HCOH I HOCH

L-Iduronic a c i d - i n heparin and heparan s u l f a t e , dermatan s u l f a t e

i

HOCH I COOH Figure 3.

Ν S0

Portion of heparin and heparin sulfates

Ο 3

S0

Ν 3

S0

Ν 3

Biosynthesis : 1. 2. 3.

P o l y m e r i z a t i o n of GlcNAc and g l u c u r o n i c a c i d N-deacp.tylated N- and O-sulfated w i t h e p i m e r i z a t i o n of some D^-glucuronic acid to L-iduronic acid.



146

PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES

The metabolism of glucuronate i n microorganisms i s q u i t e s p e c i a l , as shown by Ashwell and h i s c o l l a b o r a t o r s s e v e r a l years ago, the f i r s t step being e p i m e r i z a t i o n to D-fructuronate. In p l a n t s , Ιλglucuronate can be d i r e c t l y phosphorylated, a r e a c t i o n that does not occur i n animals. UDP-glucuronic a c i d i s a precursor of plant p o l y s a c c h a r i d e s . Glucuronate can a l s o be o x i d i z e d to the corresponding d i c a r b o x y l i c a c i d , g l u c a r i c a c i d . In animals the conversion to g l u c a r i c a c i d and the presence of the l a t t e r i n u r i n e have been demonstrated. We have already discussed the r e d u c t i o n of glucuronate to L-gulonate and i t s conversion to L ascorbate or i t s metabolism through the x y l u l o s e s . The u t i l i z a t i o n and production of g l u c u r o n i c a c i d i n v i v o are summarized below ( 7 ) :

A.

Utilization U t i l i z a t i o n i n v i v o i s extensive only i f administered as the lactone because the a c i d probably does not enter c e l l s . High extent of u t i l i z a t i o n i s i n d i c a t e d by 14

B.

1)

high y i e l d of

CO^ from l a b e l e d lactone

2)

high y i e l d of u r i n a r y L - x y l u l o s e i n the pentosuric human

Production Glucuronic a c i d production i s increased by 1)

substances

excreted as glucuronides

2)

inducers of the microsomal P-450 system (e.g. s t e r o i d s , b a r b i t u r a t e s ) . These substances a l s o increase the production of a)

L-ascorbic acid

b)

glucaric acid

The production of g l u c u r o n i c a c i d , that i s , of UDP-glucuronate, i s responsive to some inducing agents which i n c r e a s e the produc t i o n of conjugated glucuronides, of L - a s c o r b i c a c i d , and of g l u c a r i c a c i d and, I might add, of L - x y l u l o s e i n the p e n t o s u r i c human. The mechanism of t h i s i n d u c t i o n has been studied f o r many years and i s probably s t i l l not very c l e a r l y understood. Various s t e r o i d s and b a r b i t u r a t e s and other drugs which induce the micro somal P450 system are s t i m u l a t o r s of the production of glucuronic acid derivatives.


8.

Pentoses and Uronic Acids

TOUSTER

147

F i g u r e 4 shows that UDP-glucuronic intermediate i n metabolism:

a c i d i s somewhat of a key

Glucuronides


UDP-D-G lue ose»

>UDP-D-Glucuronic a c i d

UDP-^-Xylose

^ D-Glucuronic

acid

I

I L-xylulose I

V xylitol

I D-xylulose Figure 4. Reactions of UDP-O-glucuronic acid UDP-Glucuronic a c i d i s used i n the b i o s y n t h e s i s of glucuronides and proteoglycans; i t i s the precursor of g l u c u r o n i c a c i d which goes to the x y l u l o s e s and to a s c o r b i c a c i d , and i t i s the precursor of the x y l o s e found i n the g a l - g a l - x y l bridge between mucopolysaccharide chains and polypeptide chains i n proteoglycans by v i r t u e of i t s d e c a r b o x y l a t i o n to UDP-xylose. VIII.

P a t h o l o g i c a l Aspects of D-Glucuronic and L-Iduronic A c i d s

There are now two h e r e d i t a r y lysosomal diseases s p e c i f i c a l l y a t t r i b u t a b l e to d e f i c i e n c i e s i n lysosomal uronidases. Gargoylism, or H u r l e r s d i s e a s e , a s s o c i a t e d with the accumulation of dermatan and heparan s u l f a t e s and with mental d e f i c i e n c y and a v a r i e t y of morphological changes, has r e c e n t l y been shown to be due to an L-iduronidase d e f i c i e n c y i n lysosomes (22). In the l a s t few years another type of mucopolysaccharidosis has been found that has some s i m i l a r i t y to H u r l e r ' s d i s e a s e . As a r e s u l t of the work of S l y et a l . (23) and of Neufeld and her a s s o c i a t e s (24), t h i s disease, a t y p i c a l mucopolysaccharidosis, can be a t t r i b u t e d to 3 - g l u c u r o n i dose d e f i c i e n c y i n the lysosomes. In connection with lysosomal d i s o r d e r s , i t i s r e l e v a n t to mention at a symposium such as the present one that severe lysosomal storage abnormalities have been caused by the a d m i n i s t r a t i o n of undegradable polymers, i n c l u d i n g dextrans and p o l y v i n y l p y r r o l i d o n e . Great c a u t i o n should be used i n i n j e c t i n g such m a t e r i a l s i n t o humans. 1


148

PHYSIOLOGICAL

EFFECTS

O F FOOD

CARBOHYDRATES


Also known a r e abnormalities i n g l u c u r o n y l t r a n s f e r a s e , the enzyme system(s) c a t a l y z i n g the t r a n s f e r of g l u c u r o n i c a c i d from UDPGlcUA t o s u i t a b l e acceptors. In C r i g 1 e r - N a j j a r disease a d e f i ciency of g l u c u r o n y l t r a n s f e r a s e i s r e s p o n s i b l e f o r i n s u f f i c i e n t conversion of the heme degradation product b i l i r u b i n to b i l i r u b i n glucuronide, the r a p i d l y e x c r e t a b l e , more water-soluble a c i d i c form. In t h i s disease the unreacted b i l i r u b i n accumulates i n the nervous system, with d e l e t e r i o u s consequences t o the i n f a n t (25). There seems t o be an animal model of t h i s disease, the Gunn r a t , i n which s i m i l a r abnormal b i l i r u b i n metabolism i s observed as w e l l as low t r a n s f e r a s e l e v e l s . IX.

Summary and Prospects

In summary, i t i s evident that pentoses and uronic a c i d s are extremely important to mammalian b i o l o g y . I have not commented on c e r t a i n aspects of u t i l i z a t i o n of complex uronic a c i d and pentosec o n t a i n i n g polymers, such as p e c t i n s , by mammals because i n general these seem t o be p o o r l y u t i l i z e d . One area that w i l l c e r t a i n l y witness an i n t e r e s t i n g f u t u r e concerns the lysosomal storage disease because so many of the accumulated proteoglycans are r i c h i n uronic a c i d s . Indeed, s i n c e pinocytosed chemotherap e u t i c agents a r e destined to enter lysosomes, where the metabolic abnormalities a r e found, these diseases are prime t a r g e t s f o r enzyme therapy attempts. C u r r e n t l y , 3-glucuronidase i s i n f a c t being studied as a chemotherapeutic agent i n a t y p i c a l mucopolysaccharidosis .

Literature Cited

1. Rodén, L., in "Metabolic Conjugation and Metabolic Hydrolysis" (W. H. Fishman, ed.), Vol. II, pp. 345-442, Academic Press, New York (1970). 2. Hiatt, H. H., J. Biol. Chem. (1957) 224, 851-859. 3. Segal, S. and Foley, J. B., J. Clin. Invest. (1959) 38, 407-413. 4. McCormick, D. B. and Touster, O., Biochim. Biophys. Acta (1961) 54, 598-600. 5. McCormick, D. B. and Touster, O., J. Biol. Chem. (1957) 229, 451-461. 6. Hollmann, S. and Reinauer, H., Z. Ernährungswissenschaft (1971) Suppl. 11, pp. 1-7. 7. Touster, O., in "Comprehensive Biochemistry" (M. Florkin and Ε. H. Stotz, eds.), Vol. 17, pp. 219-240, Elsevier Publishing Company, Amsterdam-London-New York (1969). 8. van Heyningen, R., Biochem. J. (1958) 69, 481-491. 9. Touster, O., Fed. Proc. (1960) 19, 977-983.



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and

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Acids

149

10. Burns, J. J., in "Metabolic Pathways" (D. M. Greenberg, ed.), Vol. 1, pp. 341-356, Academic Press, New York (1960). 11. Burns, J. J. and Kanfer, J., J. Am. Chem. Soc. (1957) 79, 3604-3605. 12. Hollmann, S. and Touster, O., J. Am. Chem. Soc. (1956) 78, 3544-3545. 13. Hollmann, S. and Touster, O., J. Biol. Chem. (1957) 225, 87102. 14. Touster, O., Aronson, Ν. N., Jr., Dulaney, J. T., and Hendrickson, H., J. Cell Biol. (1970) 47, 604-618. 15. Arsenis, C., Hollmann, S., and Touster, O., Abstracts of the American Chemical Society Meeting, New York, September 1966, C-286. 16. Arsenis, C. and Touster, O., J. Biol. Chem. (1967) 242, 3400-3401. 17. Hankes, L. V., Politzer, W. M., Touster, O., and Anderson, L., Ann. Ν. Y. Acad. Sci. (1969) 165, 564-576. 18. Hiatt, H., in "The Metabolic Basis of Inherited Disease" (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds.), 3rd ed., pp. 119-130, McGraw Hill, New York, Toronto, London (1972). 19. Wang, Y. M. and van Eys, J., New Eng. J. Med. (1970) 282, 892-896. 20. van Heyningen, R., in "Proceedings of the International Sym posium on Metabolism, Physiology, and Clinical Use of Pentoses and Pentitols," Hakone, Japan, August 27-29, 1967 (B. L. Horecker, K. Lang, and Y. Takagi, eds.), pp. 109-123, Springer-Verlag, Berlin, Heidelberg, New York (1969). 21. Höök, M., Lindahl, U., Bäckström, G., Malmström, Α., and Fransson, L.-Å., J. Biol. Chem. (1974) 249, 3908-3915. 22. Matalon, R. and Dorfman, Α., Biochem. Biophys. Res. Commun. (1972) 47, 959-964. 23. Sly, W. S., Quinton, Β. Α., McAlister, W. H., and Rimoin, D. L., J. Pediat. (1973) 82, 249-257. 24. Hall, C. W., Cantz, M., and Neufeld, E. F., Arch. Biochem. Biophys. (1973) 155, 32-38. 25. Schmid, R. in "The Metabolic Basis of Inherited Disease" (J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds.), 3rd ed., pp. 1141-1178, McGraw-Hill, New York, Toronto, London (1972).


Metabolism and Physiological Effects of the Pentoses and Uronic Acids

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