NITROGENOUS WASTE PRODUCTS AND EXCRETORY ENZYMES IN THE MARINE POLYCHAETE CIRRIFORMIA SPIRABRANCHA (MOORE, 1904) INTRODUCTION Although some information is available on nitrogenous excretion in terrestrial oligochaetes, little is known about the subject in marine polychaetes. Bahl did the first consis¬ tent study on oligochaete excretion. He found that ammonia, urea, and creatinine were excreted through nephridia in the body wall. Cohen and Lewis (1950) found high arginase activity in the gut wall of Lumbricus and almost no activity in the body wall. They concluded that the earthworm utilizes the ornithine¬ urea cycle as part of its nitrogen metabolism. More recently, Needham (1960) has compared arginase activity in two oligochaetes, Lumbricus and Eisenia, in relation to the amount of urea: ammon ia excreted during feeding and fasting regimes. Needham's work supported the study done earlier by Cohen and Lewis on the earth¬ worm. In the present study done on the cirratulid polychaete, C. spirabrancha, nitrogenous excretion products have been deter¬ mined and levels of enzymes involved in nitrogen metabolism have been measured. The major waste product was found to be ammonia, which is excreted through the tentacles and anterior body wall. Urea and traces of taurine were also found in the aqueous excre¬ ta. The tissues exhibit all of the purine catabolism enzymes, uricase, allantoinase, allantoicase, and urease. Three enzymes in the ornithine-urea cycle were assayed: ornithine transcar¬ bamylase, argininosuccinate lyase, and arginase. Argininosuc¬ cinate synthetase and carbamyl phosphate synthetase were not studied. EXPERIMENTAL PROCEDURES MATERIALS Animals: Worms were collected daily from the mudflats under Fisherman's Wharf, Monterey, California. Each worm weigh¬ ed from 0.3 to 1.3 grams. The tentacles, dorsal blood vessel, body wall and gut wall were selectively removed for study. Tissues were washed in sterile sea water to remove any coelomic fluid, mucus, and gametes. The tissues were kept cold and weigh¬ ed in tared flasks. Chemicals: 1-arginine (HCl), 1-lysine (HCl), 1-aspartic acid, 1-cysteine (HCl), dl-asparagine, glycine, glycylglycine, 1-serine, 1-ornithine (HCl), 1-leucine, dl-histidine (HCl), 1¬ proline, hydroxy-1-proline, 1-cysteic acid, dl-tyrosine, 1-citrul¬ line, 1-valine, and argininosuccinate were obtained from Calbio¬ chem. L-phenylalanine, 1-glutamic acid, 1-tryptophan, alanine, cystine, dilithium carbamyl phosphate, 2,3-butanedione-2-oxime, allantoin, cetyltrimethylammonium bromide, tris (hydroxymethyl) aminomethane, and uric acid were ordered from Sigma. Ninspray and taurine came from Nutritional Biochemicals. Allantoic acid was obtained from K and K. GENERAL METHODS Collection of aqueous excreta: Fresh worms were dried for 30 seconds on Whatman no. 1 filter paper, weighed, and placed in plastic snap top vials along with 1.0 ml. of sterile sea water containing streptomycin and penicillin at 1 mg. and 0.3 mg., respectively, per ml. At every collection interval 1 ml. was drawn off and replaced by fresh sterile sea water. The sam¬ ples were analyzed for ammonia, urea, uric acid, alkaline labile amides, and hot trichloroacetic acid labile amides. Excretion 1å of free amino acids was also investigated. Analysis of free amino acids in aqueous excreta: Approx¬ imately 100 ml. of aqueous excreta (the term urine will be used to refer to aqueous excreta collected from around the worms. Bahl (1947) used similar terminology) was desalted by passing the solution through a column of Dowex-50 (H' form, 200-400 mesh). Enough Dowex-50 was used to desalt two times the number of millequivalents of monovalent cations in 100 ml. of sea water. The column was eluted with 1 N NHAOH and the pH of the effluent was monitored at all times. When the pH of the effluent changed froml.2 to 4.4, the column was washed with three bed volumes of 1 N NH,OH and all effluents combined. This amino acid frac¬ tion was evaporated to dryness in a flash evaporator and the cry¬ talline residue taken up in 1.0 ml. of distilled water. 10 ul, of amino acid extract was spotted on a 20 cm. by 20 cm. piece. of Whatman no. 1 filter paper and developed in two dimensions with n-butanol-acetic acid-water (4:1:5, the top layer of this two layer system was used as the mobile phase) as the first sol ventand n-butanol-2-butanone-water (2:2:1), with the chamber sat¬ urated with cyclohexylamine (Mizell and Simpson) as the second solvent system. A standard map was made using arginine, lysine, aspartic acid, cysteine, glutamine, asparagine, cystine, glycine hydroxyproline, alanine, proline, cysteic acid, histidine, valine, tyrosine, leucine, tryptophan, phenylalanine, glutamic acid, ser¬ ine, taurine, ornithine and citrulline. All chromatograms were developed with Ninspray. It was necessary to use only one'ad¬ ditional identification procedure: the reaction between taurine and o-phthalaldehyde followed by alcoholic KOH (Smith). Analytical methods: Ammonia was determined by a modif- 16 ication of Ternberg's (1964) method. Erlenmeyer flasks (125 ml.) fitted with rubber serum stoppers, with sleeves, were substit¬ uted for the side arm flasks suggested by Ternberg. Saturated sodium carbonate was introduced into the sealed vessel by means of a syringe. The development tabs were cut from Whatman no. 1 filter paper and in all procedures handling the paper rubber gloves were worn to avoid contamination from the skin. The method proved to be very consistent (+ 0.015 u mole NHa was the standard deviation for the urease solution used in the development of sam¬ ples containing urea and the standard deviation for the standard ammonium sulfate solution was + 0.004 u mole NH3 )and ten times more sensitive than Nesslerization. Urea was determined as the difference (endogenous ammon¬ ia + ammonia liberated by urease) minus (endogenous ammonia a¬ lone). Samples were incubated with 100 ul. of a 10% solution of urease (Matheson, Coleman, and Bell) in 30% ethanol for fif¬ teen minutes on a rotating platform. The modified Ternberg method was employed for ammonia determinations. Uric acid was determined by the colorimetric method of Sobrino-Simoes (1965). Interfering substances are glucose and ascorbic acid. Citrulline was determined by the method of Archibald (1945), It was necessary to use technical grade sulfuric acid (Ratner) filtered through glass wool. It was also found that wrapping the developing tubes in aluminum foil preserved the optical density for up to four hours. The problem of interference by allantoin and urea was avoided by filtering all samples through Whatman no. 1 filterpaper directly into a column (1 cm. by 5 cm.) of Dowex¬ 50 and isolating the citrulline according to Watts, et al. 7 Glyoxylic acid was determined by the method of Brown (1968). 2 ml. of 0.5 M HClO followed by 1 ml. of 2,4-dinitro¬ phenylhydrazine solution (50 mg./100 ml. 95% ethanol) were added to 2 ml. of sample to be analyzed and this mixture was allowed to stand at room temperature for 10 minutes to effect formation of the 2,4-dinitrophenylhydrazone of glyoxylic acid. The final color was developed by the addition of 2.50 ml. of 2.5 N NaoH with rapid mixing. The color was transient (change in O.D. of 0.200 in one hour) but reproducible when readings were taken after a fixed interval (15 minutes) for all samples. Two different methods were utilized in the determination of labile amides in the tissues of the worm. The first method was a general alkaline hydrolysis carried out in 1 N NaoH for 30 minutes at room temperature. The second method was an acid hydr; lysis taken from Harris' (1943) glutamine hydrolysis pro- cedure. Samples were digested in 10% TCA at 70 degrees for 75 minutes, cooled, brought to pH 11 in the sealed microdiffusion chamber and analyzed for ammonia. This method hydrolyzes glu¬ tamine completely. Under the same conditions asparagine gives 11% hydrolysis and urea 0.2%, whereas arginine, guanidine, guanine, adenine, creatinine, and glutamic acid liberate no appreciable amount of ammonia. The difference between total ammonia measur¬ ed after one of the two procedures and the endogenous ammonia gave a measure of the amount of bound or labile ammonia pres¬ ent in the tissue of the worm. A control was run for each method: for the alkaline hydrolysis, a tissue sample was brought to pH 11 and analyzed for ammonia. For the Harris method, hydrolysis in 10% TCA for 75 minutes was carried out at 5 degrees. Tissue homogenates: After dissection and weighing, tis- sues were extracted with 1 ml. of homogenizing media per 0.125 g of tissue. For some assays, 10% homogenates were used. Body Walls and tentacles were homogenized in a motorized teflon pes¬ tle homogenizer; guts and blood were homogenized in ground glass homogenizers. Ornithine transcarbamylase assay: The method of Brown and Cohen (1959) was modified for use with polychaete tissues. 0.5 ml. of CTB supernatant Sj and 0.25 ml. of supernatant S9 were added to 0.5 ml. 1-ornithine, pH 8.0, and 0.5 ml. Na gly¬ cylglycine buffer, pH 8.3, and the reaction started by addition of 0.5 ml. carbamyl phosphate solution. The final u molar amounts of substrates and buffers were the same as those used by Brown and Cohen. The incubation was carried out at 24 degrees (as were all enzyme assays to be described) and stopped by the addition of 5.0 ml of 0.5 M HClOA. The deproteinized sample was filter¬ ed through Whatman no. 1 filter paper and directly applied to a column of Dowex-50. Citrulline was eluted and four ml. of the effluent was analyzed according to Archibald. Argininosuccinate lyase enzyme assay: Activity was assayed by a method similar to Needham's (1960) arginase assay, with 2.0 ml. of 1.5% argininosuccinate in place of arginine as the substrate. No attempts were made to substitute a C. spira¬ brancha "Ringer" for the appropriate amount of earthworm Ringer suggested by Needham. The M/4 phosphate buffer (pH 7.4) was used for all dilutions of tissue homogenates. The endogenous arginase split any arginine formed during the incubation and the resulting urea was determined as previously described. Arginase assay: The method above was used only with the substrate being 2 ml. of a 2% solution of arginine HCl. 72 Urease assay: Some modifications of the preceding method afforded a good urease assay. Tissues were homogenized in M/4 phosphate buffer (pH 7.4), diluted to 8 ml. and 2 ml. of 1% urea were added to start the reaction. Addition of the arginase cofactor Cocly was unnecessary in this procedure. Uricase assay: The method for determining uricase was adapted from Jorgenson's (1963) procedure for the enzymatic de¬ termination of uric acid and xanthine. Tissue homogenates were prepared in 0.06 M glycine buffer (pH 9.3). 0.2 ml. of homogenate was diluted to 2.0 ml. with the same glycine buffer, The reaction was initiated by the addition of 1 ml. of 1.5 X 10-4 M uric acid solution and the resulting change in optical density was recorded on a strip chart connected to a Beckman DU Spectrophotometer with Gilford Linear Absorbance attachments. Allantoinase assay: The method of Brown (1968) was em- ployed for this assay. Homogenates were prepared with tris (hy¬ droxymethyl)aminomethane buffer (50 u moles per ml.), pH 7.8, and a standard curve was prepared with known concentrations of allantoic acid. All samples went through a heat treatment in or¬ der to cleave the allantoic acid into urea and glyoxylate and the glyoxylate was measured as previously described. Allantoicase assay: Tissues were homogenized in M/4 phosphate buffer, pH 7.4, diluted to 8.5 ml. with more phosphate buffer, and the reaction initiated by the addition of 1.5 ml. of 2% allantoic acid solution. The standard assay for urea was applied to 1 ml. samples every hour over a four hour period, Blanks run in parallel gave no increase in the amount of ammonia during the incubation period. Specific activity: specific activity will refer to 7 the number of u moles of substrate catalytically changed, or u moles of product produced, per hour under assay conditions, per gram of wet tissue. RESULTS Analysis of urine: Ammonia was found to be the primary constituent of the aqueous excreta. The level of urea ranged from 0% in most samples analyzed (73 of 75) to 3.2% (in 2 of 75 samples). It is doubtful that urea is excreted. Uric acid was below detection (less than 0.012 u mole per ml.). Incuba¬ tion of the urine in 1 N NaoH for 30 minutes gave no increase over the level of endogenous ammonia. Similarly, the glutamine hydrolysis in hot 10% TCA gave no more ammonia than in the nor¬ mally developed sample. Thus, labile amides in the urine are not detectable and are assumed to be negligible. The rate of ammonia output, in u moles/hour/g wet tissue, does not significantly fluctuate over a 36 hour period nor does it fluctuate over a shorter time period of 14 hours. Table 1 summarizes these results. The results of the chromatographic study done on the urine indicate that amino acids are not actively excreted by C. spirabrancha. Only one compound gave a positive ninhydrin test after the desalted urine concentrate was separated in two dimensions: taurine was identified by matching it with the a¬ ppropriate spot on the map and proof of identification was made by the unknown reacting with o-phthalaldehyde in acetone followed by alcoholic KOH, giving the red color characteristic of taurine, One other detectable substance with a very low Re (less than 0.05) was not identified, but it was assumed to be an arginine type compound (Re arginine=0.07) such as taurocyamine. Anatomical location of nitrogenous waste products in different tissues; The blood, tentacles, body wall, gut wall and aqueous gut con¬ tents of C. spirabrancha were analyzed for ammonia and urea in both fresh worms and in worms fasting for one week. The same tissues were assayed for uric acid, citrulline and two kinds of labile amides. Results are summarized in Table 2. The tentacles and gut wall show marked drops in ammonia levels upon inanition while the level in the body wall shows a small decrease and the level in the blood rises. The urea level in the tentacles, body wall, and gut wall drops greatly, while the level of urea in the blood drops less markedly. The level of ammonia and both al¬ kaline and acid labile amides are conspicuously high in the tent¬ acles. The gut wall, blood and body wall have much lower levels of ammonia, descending in that order, and the ammonia content of the gut contents is very low. Basic hydrolysis of the blood, body wall and tentacles released more bound ammonia than the acid hy¬ drolysis, whereas the opposite situation is true in the gut wall. Urea in the blood proved to be approximately twice the level found in the three other tissues. The uric acid was very high in the blood, much lower in the tentacles and gut wall, and below detec¬ tion in the body wall and aqueous gut contents (less than 0.095 u mole per gram of tissue). Enzyme activities in different tissues: Three enzymes of the ornithine-urea cycle were examined. Ornithine transcarbamyl¬ ase has the highest specific activity (71.6) of any of the three enzymes. The blood contains the greatest cumulative activity of all three of the enzymes. Table 3 summarizes the specific activ¬ ities of ornithine transcarbamylase, argininosuccinate lyase, and arginase. All of the enzymes involved in purine catabolism were examined and allantoinase in the blood has the highest specif¬ ic activity (66.50). It appears that both uricase and allanto¬ icase are both limiting in C. spirabrancha. Table 3 summarizes the specific activities of these enzymes. DISCUSSION It is clear that the ammonia excreted by C. spirabrancha comes from two sources: the first being the deamination of amino acids, such as glutamine or other labile amides, which occur in especially high levels in the tissues associated with excretion (predominantly the tentacles and, to a lesser extent, the anter¬ ior body wall. This topic will be discussed in detail later in the discussion.). The second source is purine catabolism. This polychaete seems to have beneficially compartmentalized various steps in the degradation of purines to ammonia. The blood poss¬ esses the highest uricase and allantoinase activities and the lowest allantoicase activity, 9.13, 66.50, and 3.72, respect¬ ively. This suggests that mainly non-toxic degradation occurs within the main body of the worm, while at the site of excretion, the high levels of allantoicase and urease convert the allantoic acid completely to ammonia, which then leaves the body or becomes bound as a non-toxic amide such as glutamine. The latter fate of the ammonia is highly likely because the rate of ammonia excre¬ tion is fairly constant and this would demand a regulation sys¬ tem which would internally control the endogenous ammonia. It is of interest to note that the two limiting en¬ zymes in the purine cycle, uricase and allantoicase, have very sim¬ ilar maximum rates, 9.13 and 9.15, respectively, and occur in the ratio of about 1:6 when compared to the non-limiting enzyme, allan¬ toinase. The study done by Brown, et al. (1966) on the purine cycle enzymes in the liver of the African lungfish yields similar re¬ 176 lationships. Both limiting enzymes have very similar activities, 1.27 and 1.25, and the ratio between limiting enzyme and the en¬ zyme in excess is roughly 5. Perhaps these similarities are characteristic of organisms utilizing a purine cycle. This speculation will require much comparative work for justification. The possibility that the ornithine-urea cycle is function¬ al in C. spirabrancha cannot be dismissed. Ornithine transcar¬ bamylase in the blood has the highest activity of any enzyme assayed and argininosuccinate lyase and arginase are also def¬ initely present. Neither carbamyl phosphate synthetase nor ar¬ gininosuccinate synthetase were studied. The unusually high ac¬ tivity of ornithine transcarbamylase compared with the other two enzymes studied and the multiplicity of metabolic functions of the intermediates in the ornithine-urea cycle suggest many other possibilities for the presence of these enzymes than for strictly the synthesis of urea. The arginase may be present in conjunc¬ tion with arginine phosphagens or it may serve to catalyze the breakdown of ingested arginine to urea. In addition, 1-ornithine can react with + -keto-glutarate (Bernfield) to eventually form 1-proline and carbamyl phosphate can act as a precursor in pyr¬ imidine biosynthesis through the intermediate uridylic acid. The high concentration of endogenous citrulline strongly suggests a conventional role for the ornithine cycle enzymes. The presence of the cleavage enzyme strengthens the argument and also suggests that the limiting enzyme is the condensing enzyme a high citrulline concentration). The distribution of urease in the four tissues studied illustrates a rational scheme for choosing the sight of ammonia excretion. The internal tissues, the blood and gut wall, are very low in urease activity and very high in enzymes necessary (thus for biosynthesis of urea or its immediate precursors, while the external tissues, the tentacles especially and the anterior body wall, have very high urease activity. The proposed anatomical sites of excretion correlate well with the general behaviour of the worm and the descriptive anatomy of the nephridia. The worm lives in a mucus burrow im¬ pacted in black, sulfide mud, and it waves its tentacles in the circulating fresh sea water above the mud. Excretion of nitrogen ous wastes through the tentacles, which have a very large sur¬ face area, would not expose the worm to high concentrations of toxic ammonia within the stationary burrow. The single pair of nephridia (Gilbert) are located ven¬ trally behind the first septum and extend posteriorly 3 to 5 seg¬ ments. The internal funnel is highly ciliated, giving each nephridium the power to circulate a great quantity of fluid. Each nephridium is intensely vascularized and possesses a large nephridiopore (25-30 u in diameter). This proposed site of ex¬ cretion, the anterior body wall, would also allow dilution of tox¬ ic ammonia by the shifting sea water above the worm. The maintainence of the ammonia level in the blood of a fasting worm suggests that the blood contains most of the bio¬ synthetic machinery involved in nitrogen homeostasis, whereas the body wall and tentacles mainly rids the body of nitrogenous wastes. The finding of taurine as the only constituent besides ammonia and a small amount of urea in the urine is perfectly reasonable when one considers that 3% of the body wall's weight is taurine (Luck) and some leakage can be expected. There is no comparative literature on this subject ex¬ cept for the studies done on oligochaetes. Since the environ¬ 126 ments are so diverse, a comparison would not be meaningful. SUMMARY 1. C. spirabrancha primarily excretes ammonia, abng with trace amounts of urea and taurine. No amino acids were found to be excreted. 2. Studies of uricase, allantoinase, allantoicase, and urease suggest that the ammonia primarily results from a urico- lytic pathway. 3 The presence of ornithine transcarbamylase, arginino¬ guccinate lyase, arginase and citrulline in the tissues strongly suggest a functional ornithine-urea cycle. 4. Glutamine-like labile amides present in the greatest amounts in the tissues associated with excretion support the idea that amino acid deamination may also play a role in the formation of ammonia. 5. The rate of ammonia excretion in this sedentary polychaete is relatively constant. 6. The ammonia content of the aqueous gut contents is very low, which suggests that there is no enteronephric excretion. 7. The most probable sites of excretion are the tent¬ acles and, to a lesser extent, the anterior body wall, which con¬ tains a single pair of large nephridia. This hypothesis is sup¬ ported by biochemical assays done on the tissues, by behavioural studies and by descriptive anatomy of the nephridia. 8. Following inanition, the levels of ammonia and urea drop markedly in the tissues associated with excretion and main¬ tain their levels in the tissues associated with the bulk of the catabolic machinery. 17 ACKNOWLEDGEMENTS I would like to thank Prof. David Epel and John Phillips for the time they spent with me and for their helpful suggestions, Tom Gilbert's description of C. spirabrancha nephridia was greatly appreciated as was the allantoinase assay procedure sent to me by Prof. G.W. Brown. This work was supported by the Undergrad¬ uate Research Program of the National Science Foundation, Grant 4369. 86 time of collect¬ ion¬ in hours 12 18 24 30 36 number of samples 5 5 5 TABLE 1 u moles time of collect¬ of ammon ion¬ ia excre ted per in hours hour per gram wet tissue 0.128 0.164 0.155 6 8 0.210 0.166 10 0.168 12 14 number samples 5 u moles of ammon¬ ia excre¬ ted per hour per gram wet tissue 0.214 0.142 0.143 0.150 0.096 0.101 — 0.128 18 Tissue: u mole of endogenous compound / gram wet tis sue ammonia ammonia-af¬ ter fasting lor / days urea urea-after fasting for days citrulline uric acid alkane drolysis 1 N NaoH alkaline con trol-pH 1l acid hydrol¬ vsis in hot 10% TCA acid control cold 10% TCA entacles 30.35 23.94 3.32 1.22 4.36 1.34 85.76 19.01 67.65 8.30 TABLE 2 blood body wall 11.48 7.88 12.48 7.13 6.38 3.74 4.88 O.37 5.82 2.62 below 4.15 detection 24.39 32.28 no increaße 2.94 over en¬ dog. NII3 11.36 3.71 no incr. no incr. gut wall 14.94 9.77 3.56 0.71 2.23 1.01 18.18 no incr. 39.98 no incr. aqueous gut contents 2.65 — below detectior 6.06 no incr. 5.00 no incr. 182 90 8 7 60 50 •— J 40 30 20 10 oo FIGURE 1 k 40 20 minutes 60 BLOOD GUT WALL BODY WALL TENTACLES 8 O E 1.80 1.6( 0.20 0 FIGURE 2 ENTACLES 40 20 60 minute: 6.00 03 E2.0 1.33 O.67 0 O 20 min FIGURE 3 „BLOOD TENTACLES GUT WALL 60 40 10 5. 7.( 6.0 O O 3.00 2.00 1.00 18 FIGURE 4 TENTACLES BODY WALL „BLOOD 40 60 20 minutes 9.00 8.0 6.0 5.0 4.0 9 O -3.00 2.00 1.00 oL FIGURE 5 40 20 minutes 60 BLOOD BODY WALL TENTACLES GUT WALL 2. 6.( 518.0 12.0 6.0 0 FIGURE 6 40 BLOOD SUE NLL BODY WALL TENTACLES — 60 20 minutes 25 o4.0 0 2.00 1.00 0 — 40 60 20 minutes FIGURE 7 8 „BODY WALL TENTACLES BLOOD-GUT WALL Tissue: Enzyme: ornithine ranscar bämylase argininosuc- cinate split ing enzyme arginase urease uricase allantoinase allantoicase tentacles 10.3 1.16 3.62 9.89 3.81 5.25 4.50 blood 71.6 5.55 2.66 9.13 66.50 TABLE 3 body wall 25.4 0.39 1.34 8.52 4.81 5.25 9.15 gut wall 31.3 3.07 2.30 1.75 23.87 blood and guts — 3.72 96 Figure and Table Legends Table 1. Rates of ammonia excretion (in u moles/hour/gram live body weight) in C. spirabrancha. The data shown are the average of the number of experiments done within each collection period. Table 2. u molar amounts of endogenous nitrogen containing compounds in the fractionated tissues of C. spira¬ brancha. The specific activity (defined as u moles of sub¬ Figure 1. strate catalytically changed, or u moles of product produced, per hour under assay conditions per gram wet tissue.) of ornithine transcarbamylase given in u moles of citrulline produced per hour per am wet tissue weight. The specific activity of argininosuccinate cleavage Figure 2. enzyme given in u moles of arginine produced per hour per gram wet tissue weight. Figure 3. The specific activity of arginase in u moles of arginine utilized per hour per gram wet tissue. Figure 4. The specific activity of urease in u moles of urea utilized per hour per gram wet tissue. Figure 5. The specific activity of uricase in u moles of uric acid utilized per hour per gram wet tissue. The specific activity of allantoinase in u moles Figure 6. of allantoic acid produced per hour per gram wet tissue. The specific activity of allantoicase in u moles Figure 7. of urea produced per hour per gram wet tissue. A numerical summary of the specific activities of Table 3. the enzymes shown in figures 1 through 7. All values have the units u moles substrate or pro¬ duct per hour per gram wet tissue. 10 92 BIBLIOGRAPHY Archibald, R.M. (1944) Determination of Citrulline. J. Biol Chem. 156, 121-141. Bahl, K.N. (1947) Excretion in the Oligochaetes. Biol. Rev 22, 109-147. Bergmeyer, H.U., et al. (1963) Methods of Enzymatic Analysis. Academic Press Bernfield, P., et al. (1967) Biogenesis of Natural Compounds. Pergamon Press. Brown, G.W., and Cohen, P.P. Quantitative assay of urea cycle enzymes. J. Biol. Chem. 234, 1769 (1959) Brown, G.W., et al. Uricolytic enzymes. Science. 153, 1653. (1966) Brown, G.W. Personal communication. (1968) Cohen, S. and Lewis, H.B. (1949) The nitrogenous metabolism of the earthworm (Lumbricus terrestris). J. Biol. Chem. 180, 79-91. Cohen, S. and Lewis, H.B. (1950) The nitrogenous excretion of the earthworm II. Arginase and urea synthesis. J. Biol. Chem. 184, 479-484. Dales, P.R. (1963) Annelids. Hutchinson University Library. Gilbert, T. (1968) Unpublished work on C. spirabrancha nephridia. Harris, M.M. (1943) Assay of glutamine in brain homogenates. J. CLin. Invest. 22, 569 Harrow, B. and Mazur, A. (1966) Textbook of Biochemistry. W.B. Saunders co. Holden, J.T., et al. (1962) Amino Acid Pools. Elsevier Publ. Co. Luck, J.M. and Kurtz, A.C. (1935) Studies on annelid muscle. I Taurine in Adouina spirabranchus. J. Biol. Chem. 111,577-584. M. and Simpson, S. Chromatography of Amino Acids. Mizell, J. Chromatog. 5, 157-160. A.E. (1957) Components of nitrogenous excreta in earthworms. Needham J. Exp. Biol. 34,425-446. Needham, A.E. (1960) Arginase activity in tissues of earthworms. J. Exp. Biol. 37, 775-782. Ratner, S., in S.P, Colowick and N.O. Kaplan (Editors). Methods in enzymology, Vol. III, Academic Press, 1957 p. 356. 19 BIBLIOGRAPHY, cont. Richter. (1948) The ammonia and glutamine content of the brain. J. Biol. Chem. 176, 1199-1210. Smith, I. (1960) Chromatographic and Electrophoretic Techniques Vol I. p. 100. Sobrino-Simoes, M. (1965) A sensitive method for the measurement of serum uric acid using hydroxylamine. J. Lab. Clin. Med. 65, 665-668. Ternberg, J.L. (1964) Colorimetric Determination of Blood Ammonia. J. Lab. & Clin. Med. 56, 766-776. Watts D.C., et al. (1965) Determination of citrulline and urea in a mixture containing sucrose. Biochem J. 96, 6c-7c.