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*(L)-METHIONINE
© 2007 American Society for Nutrition J. Nutr. 137:1868-1873, August 2007

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

2-Keto-4-(Methylthio)Butyric Acid (Keto Analog of Methionine) Is a Safe and Efficacious Precursor of L-Methionine in Chicks1,2

Ryan N. Dilger3, Christoph Kobler4, Christoph Weckbecker4, Dirk Hoehler5 and David H. Baker3,*

3 Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801; 4 Degussa GmbH, Duesseldorf, Germany; and 5 Degussa Corporation, Kennesaw, GA 30144

* To whom correspondence should be addressed. E-mail: dhbaker{at}uiuc.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Relative bioefficacy and toxicity of Met precursor compounds were investigated in young chicks. The effectiveness of DL-Met and 2-keto-4-(methylthio)butyric acid (Keto-Met) to serve as L-Met precursors was quantified using Met-deficient diets of differing composition. Efficacy was based on slope-ratio and standard-curve methodology. Using L-Met as a standard Met source added to a purified diet, DL-Met and Keto-Met were assigned relative bioefficacy values of 98.5 and 92.5%, respectively, based on weight gain. Relative bioefficacy values of 98.5 and 89.3% were assigned to DL-Met and Keto-Met, respectively, when chicks were fed a Met-deficient, corn-soybean meal-peanut meal diet. Thus, both DL-Met and Keto-Met are effective Met precursor compounds in chicks. Additionally, growth-depressing effects of L-Met, DL-Met, and Keto-Met were compared using a nutritionally adequate corn-soybean meal diet supplemented with 15 or 30 g/kg of each compound. Similar reductions in weight gain, food intake, and gain:food ratio were observed for each compound. Subjective spleen color scores, indicative of splenic hemosiderosis, increased linearly (P < 0.01) with increasing intakes of each compound, suggesting a similarity in overall toxicity among these compounds. Because conversion of Keto-Met to L-Met in vivo merely requires transamination, Keto-Met may prove to be a useful supplement not only in food animal production, but also as a component of enteral and parenteral formulas for humans suffering from renal insufficiency.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Crystalline Met has been an important feed supplement in production animal agriculture for many years. The global production of Met and Met analog compounds exceeded 600,000 metric tons in 2005 (1). Assuming a mean price of $2.93/kg, this production volume translates to annual sales of nearly $1.8 billion for Met compounds, being second in volume only to crystalline Lys. Although the vast majority of crystalline Met is used to supplement animal feeds, the potential also exists to use Met compounds in human nutrition and clinical medicine. Generally, Met compounds have been of limited use as dietary supplements for humans due to their undesirable organoleptic properties. Moreover, humans use the D-isomer of Met inefficiently (2,3), unlike food animals for which synthetic DL-Met is an important commercial product. There are physiological states, however, where Met precursor compounds could be useful if proven both effective and economical.

Human disease states characterized by renal insufficiency are often accompanied by nitrogen accumulation (i.e., uremia). Such conditions can benefit from preventative nutritional therapies, including reduced nitrogen intake to minimize excretion of nitrogenous waste products (4). The use of nitrogen-free amino acid precursors has long been proposed as an effective solution (5,6), but the impetus to conduct research on such compounds has been somewhat stymied by the overwhelming preference of physicians to rely on dialysis. Both the hydroxy and keto analogs of Met are potentially useful as supplements for uremic patients receiving either enteral or parenteral formulas (7,8).

In vivo conversion of Met hydroxy analog [DL-2-hydroxy-4-(methylthio)butyric acid] to 2-keto-4-(methylthio)butyric acid, i.e., Keto-Met, requires 2 separate enzymes (9): D-2-hydroxy-acid dehydrogenase (EC 1.1.99.6) and L-{alpha}-hydroxy acid oxidase (EC 1.1.3.15). The resulting intermediate, Keto-Met, is then transaminated to L-Met. Direct chemical synthesis of Keto-Met has been attempted on several occasions throughout history (10–12), but industrial large-scale production has never been realized. Hence, a dearth of knowledge exists regarding the effectiveness of Keto-Met as a precursor for Met. Specifically, accurate quantitative estimates of Keto-Met bioefficacy and toxicity are lacking. Elucidating the efficacy of oral Keto-Met is necessary if this compound is to be used commercially as a precursor of L-Met for animals and humans.

Our primary objective was to quantify the bioefficacy of 2 Met precursor compounds (DL-Met and Keto-Met) using the chick as an animal model. This was accomplished using Met-deficient diets based on either purified ingredients or ingredients providing intact proteins typically used in animal agriculture. Our second objective was to compare the relative toxicity of excess L-Met, DL-Met, or Keto-Met when added to a diet adequate in sulfur amino acids.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
All procedures were approved by the University of Illinois Animal Care and Use Committee. Four assays were conducted using male chicks (New Hampshire male x Columbian female) obtained from the University of Illinois Poultry Farm. Chicks were housed in thermostatically controlled starter batteries with raised-wire flooring in an environmentally controlled room with continuous lighting. From hatch to d 7 posthatch, chicks were fed a 230 g/kg crude protein (CP) corn-soybean meal starter diet adequate in all dietary nutrients (13). After being food deprived overnight, chicks were weighed, wing-banded, and randomized to dietary treatments on d 8 such that mean initial pen weights and weight distributions were similar across treatments.

Two separate basal diets were formulated to assess bioefficacy of Met precursor compounds in Assays 1–3. Chicks fed these basal diets showed poor growth due to dietary Met deficiency; supplementation with L-Met and Met precursor compounds elicited a marked improvement in chick growth performance. A purified amino acid-based diet, formulated to be singly deficient in Met, was used for Assays 1 and 2 (Table 1). This diet was analyzed (14,15) and found to contain 1.2 g/kg Met and 3.2 g/kg Met + cyst(e)ine. The supplemental Met requirement of chicks fed this purified diet was previously determined to be 1.2 g/kg (2.4 g/kg total Met) in the presence of adequate dietary cyst(e)ine (15). The basal diet used for Assay 3 was a low-protein corn-soybean meal-peanut meal diet (181 g/kg CP) solely deficient in Met (2.5 g/kg analyzed Met). In Assay 4, a standard 230 g/kg CP corn-soybean meal diet (Table 1), adequate in all dietary nutrients (13), was used to evaluate the relative effects of ingesting excess Met and Met precursor compounds. A single source of each protein-furnishing ingredient was analyzed and used throughout these 4 chick bioassays.


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  		TABLE 1 Composition of experimental basal diets

 
Experimental diets and tap water were freely available to chicks at all times. Chicks were fed for a total of 9 d in Assays 1 and 4 (d 8–17 posthatch) and 12 d in Assays 2 and 3 (d 8 to 20 posthatch). Body weight of individual chicks and pen food intakes were measured at the termination of each chick assay. Weight gain, food intake, and food efficiency (gain:food ratio) were calculated for each replicate pen of chicks.

    Met precursor compounds. Two Met precursor compounds were tested for their relative bioefficacy and toxicity in the young chick. The first, DL-Met, was produced through chemical synthesis and thus, contained an equal racemic mixture of the D- and L- isomers of Met. The second Met precursor compound was the Ca-salt of Keto-Met (Fig. 1). This compound contained 2 mol Keto-Met/mol of Ca. The Keto-Met used in these chick assays was synthesized from methylmercaptan and methyl acrylate according to procedures described previously (12,16).


Figure 1
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  		FIGURE 1  Structure of 2-keto-4-(methylthio)butyric acid, Ca salt.

 
In each chick assay, Met precursor compounds were supplemented at levels isosulfurous to L-Met. Dietary supplementation of DL-Met was based on a product guarantee for Assays 1 and 2; DL-Met was assumed to be 99.0% pure (1% H2O plus impurities). However, chemical analysis following Assay 2 revealed that DL-Met was in fact 100% pure and therefore supplemented at levels equal to L-Met in Assays 3 and 4. As a pure compound, DL-Met contains 21.49% sulfur, identical to L-Met. Multiple linear regression analyses in Assays 1 and 2 were modified to reflect the fact that DL-Met was 100% pure. Because Keto-Met contains 2 mol compound/mol Ca, it cannot be considered pure. Based on chemical analysis, the Keto-Met used in these assays was 73.0% pure (27% H2O plus impurities, including Ca) and was calculated to contain 15.68% sulfur.

    Assay 1. The objective of this 9-d assay was to determine the bioefficacy of DL-Met and Keto-Met relative to L-Met in supporting chick growth performance. The basal diet was supplemented with 0, 400, or 800 mg/kg L-Met or an isosulfurous level of DL-Met or Keto-Met at the expense of cornstarch. The basal diet contained adequate cyst(e)ine (14,15) and was therefore singly deficient in Met. Based on previous work in our laboratory (15), the doses of Met compounds used were expected to result in a linear growth response. A standard slope-ratio analysis was conducted to determine the bioefficacy of Met precursor compounds relative to L-Met.

    Assay 2. Similar to Assay 1, the objective of this 12-d assay was to quantify the bioefficacy of Keto-Met, but DL-Met was used as the standard Met compound in this assay instead of L-Met. Both DL-Met and Keto-Met were supplemented at concentrations isosulfurous to 400, 800, and 1200 mg/kg L-Met. Slope-ratio methodology was again used to determine a bioefficacy value for Keto-Met.

    Assay 3. This 12-d assay was designed to quantify DL-Met and Keto-Met bioefficacy in an intact-protein diet more typical of that used in the poultry industry. Similar to Assay 1, the objective here was to determine the effectiveness of DL-Met and Keto-Met relative to L-Met for support of chick growth performance. L-Met was supplemented at 0, 250, 500, and 750 mg/kg at the expense of cornstarch. This L-Met series produced a standard response curve to which DL-Met and Keto-Met were compared at a single level isosulfurous to 500 mg/kg L-Met. Using standard-curve methodology, bioefficacy values were estimated for DL-Met and Keto-Met.

    Assay 4. The objective of this assay was to compare the relative effects of ingesting excess concentrations of L-Met, DL-Met, and Keto-Met. Each Met compound was added to the nutritionally adequate, corn-soybean meal basal diet at levels isosulfurous to 15 and 30 g/kg L-Met by replacing cornstarch. In addition to quantifying growth performance, a subjective spleen color score was used to evaluate the noxious effects of excess Met and Met precursor compounds. Subjective scoring of spleen color in chicks having received excess Met correlates well with spleen Fe content (17). Upon terminating Assay 4, chick spleens were scored according to a discrete 4-point color scale as follows: 1 = red-pink (normal), 2 = dark red, 3 = red-black, 4 = black.

    Calculations and statistical analysis. All data were subjected to ANOVA using the General Linear Model procedure of SAS (18). Data were analyzed using pen means with procedures appropriate for a completely randomized design. Data are presented as mean values with pooled SEM estimates, and significance was set at {alpha} = 0.01. In each assay, response criteria (e.g., weight gain, gain:food ratio) were evaluated using orthogonal polynomial single df contrasts.

In Assays 1 and 2, the relative bioefficacy of Met precursor compounds was evaluated using standard slope-ratio methodology (19,20). Briefly, growth performance criteria (dependent variables) were regressed on supplemental sulfur intake (independent variable) from Met compounds in a multiple linear regression analysis using the General Linear Model procedure of SAS. Relative bioefficacy was then evaluated by dividing the response slope of each Met precursor compound by the response slope obtained for the standard Met compound (L-Met, Assay 1; DL-Met, Assay 2) and multiplying by 100.

Relative bioefficacy in Assay 3 was determined using an L-Met standard curve. Regression of growth performance criteria (dependent variables) on supplemental sulfur intake (independent variable) from the L-Met series of diets resulted in a simple curvilinear (quadratic) response curve. Supplemental sulfur intake from DL-Met or Keto-Met was calculated from the L-Met standard curve using overall mean weight gain and gain:food values for each Met precursor compound. This calculated quantity of supplemental sulfur intake was then divided by the mean total sulfur intake for each Met precursor compound and multiplied by 100 to obtain bioefficacy estimates for DL-Met and Keto-Met.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Assay 1. Weight gain, food intake, and gain:food ratio were increased linearly (P < 0.01) due to supplemental sulfur intake from L-Met, DL-Met, or Keto-Met (Table 2). Multiple linear regression analysis using weight gain as the dependent variable provided relative bioefficacy values of 98.5 and 92.5% for DL-Met and Keto-Met, respectively. Similar bioefficacy estimates were obtained when gain:food served as the dependent variable. The R2 values for linear regressions based on weight gain and gain:food ratio were 0.98 and 0.93, respectively.


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  		TABLE 2 Efficacy of Met precursor compounds for chicks fed a purified cyst(e)ine adequate, Met-deficient diet (Assay 1)1

 
    Assay 2. Similar to Assay 1, weight gain, food intake, and the gain:food ratio each responded linearly (P < 0.01) to incremental sulfur intake from each Met compound (Table 3). Using a 4-point multiple linear regression, this assay resulted in bioefficacy estimates of 95.2 and 97.2% for Keto-Met relative to DL-Met when weight gain and gain:food, respectively, served as the dependent variables. The R2 values for linear regressions based on weight gain and gain:food ratio were 0.96 and 0.88, respectively.


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  		TABLE 3 Efficacy of Keto-Met for chicks fed a purified cyst(e)ine adequateMet-deficient diet (Assay 2)1

 
    Assay 3. Chick growth performance responded quadratically (P < 0.01) to supplemental sulfur intake from L-Met in this 12-d assay (Table 4). Weight gain data for L-Met were fitted to a simple quadratic regression to produce a standard curve (r2 = 0.80). Improvements in weight gain due to supplemental sulfur intake from DL-Met and Keto-Met resulted in bioefficacy estimates of 98.5 and 89.3%, respectively. When gain:food ratio served as the dependent variable, bioefficacy estimates for DL-Met and Keto-Met were 115.1 and 88.1%, respectively, but the r2 was only 0.67.


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  		TABLE 4 Efficacy of Met precursor compounds for chicks fed a Met-deficient corn-soybean meal-peanut meal diet (Assay 3)1

 
    Assay 4. Ingestion of nutritionally adequate diets containing excess concentrations of each Met compound resulted in linear (P < 0.01) reductions in weight gain, food intake, and gain:food ratio (Table 5). When supplying excess Met at 30 g/kg or an isosulfurous concentration of Keto-Met, each compound reduced (P < 0.01) weight gain more than 65%. Additionally, spleen color scores increased linearly (P < 0.01) with graded excess increments of each Met compound.


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  		TABLE 5 Relative toxicity of excess dietary Met precursor compounds (Assay 4)1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
To our knowledge, we provide, for the first time, strong quantitative evidence that Keto-Met is both a safe and efficacious precursor of L-Met. The addition of Met compounds to a purified diet known to be singly deficient in Met (15) resulted in linear improvements in the growth performance of young chicks. Thus, slope-ratio methodology was used to provide quantitative bioefficacy estimates for Met precursor compounds. Because Keto-Met has potential uses as a Met precursor in both human clinical medicine (4–6,8) and production animal agriculture, quantification of its effectiveness and safety is necessary. Although some may question our use of the chick as a model, we believe this species is highly pertinent to the study of Keto-Met because: 1) the chick is highly sensitive to nutrient deficiencies due to its rapid growth rate, 2) poultry account for ~70% of all Met compounds used in production animal agriculture, and 3) chicks, unlike rats, do not practice coprophagy, a potentially confounding factor in studies of precursor efficacy.

That Keto-Met may have Met-sparing activity in the growing rat was first suggested by Patterson et al. (21) in 1936, and this qualitative assessment was confirmed some years later by Cahill and Rudolph (10) using the Na salt of Keto-Met. Claims from these early studies were based on a diet containing 15% arachin (the primary globulin in peanuts), which was supplemented with a single-dose level (4.5 g/kg) of DL-Met or an equivalent quantity of pure Keto-Met. Although rat growth was improved by the addition of either Met compound, estimating quantitative bioefficacy was impossible. Moreover, interpretation of these early studies is difficult due to: 1) the lack of detail regarding sources and levels of key nutrients in the diets used, and 2) provision of Met compounds well above the level required for maximal growth of rats fed a purified diet. Assuming a liberal Met requirement of 3.5 g/kg when fed a purified diet, these rats would have received Met at 30% above the requirement. Therefore, under these dietary conditions, Keto-Met would have resulted in rat growth equal to L-Met even with a relative bioefficacy of 78%.

A similar attempt to qualitatively study the replacement of L-Met with Keto-Met was made by Chow and Walser (22) in 1974. Although the basal diet was well defined, indispensable but not dispensable amino acids were included in their basal diet, again leading to interpretive problems (23,24). Even more striking was the fact that Keto-Met (Na) replaced an equimolar quantity of L-Met when included at 10.0 g/kg; nearly 3 times an assumed Met requirement of 3.5 g/kg. Thus, although Keto-Met may have been as low as 35% effective as a Met precursor, these authors suggested that Keto-Met could fully replace L-Met. Prior to our work, only one semiquantitative value for Keto-Met bioefficacy had been done (25); our laboratory suggested Keto-Met was 83% effective at supplying L-Met based on chick weight gain. Considering that Keto-Met was first synthesized and studied 65 y ago, we were frankly surprised to learn how few Keto-Met bioefficacy studies had been conducted.

We obtained bioefficacy estimates (relative to L-Met) for Keto-Met ranging from 89.3 to 92.5% based on either the rate or efficiency of chick weight gain. From a metabolic perspective, it seems almost intuitive that Keto-Met should be a highly effective source of Met; conversion simply requires a single transamination reaction, with in vitro studies suggesting Gln serves as the predominant amino donor (26,27). The Keto-Met compound used in our studies was the Ca-salt; thus, 2 mol of pure Keto-Met was associated with 1 mol of Ca. Therefore, Keto-Met contained impurities including H2O and Ca, but comparisons between L-, DL-, and Keto-Met were always made on an isosulfurous basis. This is the most accurate way to compare Met products, because all commercially available Met products contain a methylthiol moiety. There are reports in the literature where Met compounds were erroneously compared on an isomolar basis, even though the test compound was synthesized as the Ca-salt; this terminology is misleading and should be eliminated for the sake of clarity.

We have confidence in our bioefficacy estimates because of good agreement among the 3 assays, despite using basal diets of different composition and different estimation procedures. Moreover, bioefficacy estimates based on weight gain were similar to those based on gain:food ratio. Based on chick weight gain in Assay 2, a bioefficacy value of 95.2% was obtained for Keto-Met relative to DL-Met. Considering DL-Met, bioefficacy was 98.5% in Assays 1 and 3, which translates to a theoretical Keto-Met bioefficacy of 93.8% relative to L-Met, which is only slightly higher than the 92.5% value obtained in Assay 1. It should be noted that the 95% CI for all Keto-Met bioefficacy values reach a value of 100%. Therefore, our conclusion that Keto-Met is an efficacious source of L-Met was confirmed in all 3 bioassays.

The D-isomer of Met is well utilized by most animal species (2,3,28–31) but not by apes or humans (32,33). It has been generally accepted that the chick can use D-Met with 90% efficiency. Thus, because DL-Met is produced by chemical synthesis and is a 50:50 mixture of the D- and L-isomers, it has been assumed that DL-Met is utilized with 95% efficiency. Our work herein, however, suggests the bioefficacy of DL-Met may be closer to 99% relative to L-Met. Undeniably, quantifiable estimates of Met bioefficacy are affected by a number of factors, including the estimation methodology used, ingredient composition of the basal diet, degree of Met deficiency in the basal diet, and range of supplemental Met levels used in individual studies. However, the data in Tables 2 and 4 provide strong evidence that DL-Met is used almost as effectively as L-Met in chicks. Moreover, a direct comparison of DL-Met and Keto-Met was important because DL-Met is the primary form of synthetic Met used in animal nutrition (1). Further studies are required to determine how dietary factors (e.g., Met:Cys ratio) affect utilization of Met isomers in animals.

The ingestion of Met above dietary requirements has been shown to depress growth and cause tissue damage (2,34–37). Previous comparisons among D-Met, L-Met, DL-Met, and 2-hydroxy-4-(methylthio)butyric acid (hydroxy analog of Met) showed some differences between the chiral enantiomorphs (37–39) but less of the growth-depressing effects of Met hydroxy analog (38). In our study, L-Met, DL-Met, and Keto-Met each depressed growth equally when supplemented to a nutritionally adequate diet at 2 levels of excess. Moreover, gross examination of chicks revealed darkened spleen color scores, which corresponded with the reduction in chick growth. Splenic hemosiderosis leads to the accumulation of heme Fe and darkening of the spleen; this is a hallmark sign of Met toxicity (17,40,41). Thus, our bioefficacy and toxicity data are complementary, suggesting that Keto-Met is converted to L-Met in vivo and is therefore a viable precursor compound in chicks.

That Keto-Met was no more growth depressing than L-Met is evidence that the transamination reaction is efficient and has the capacity to handle large metabolic excesses. It was previously suggested that the ingestion of Keto-Met may lead to the production of toxic metabolites, including 3-methylthiopropionate and methylmercaptan, via an alternate pathway (40,41). The alternate pathway essentially serves an "overflow" mechanism in which excess Met is converted to Keto-Met, with subsequent oxidative decarboxylation to 3-methylthiopropionate. Because the ingestion of excesses of each of the 3 Met compounds studied resulted in similar anorexic and spleen effects in chicks, we concluded that Keto-Met is no more toxic than L-Met. Although the toxic effects of Met products have been studied extensively, more research is required to elucidate the exact mechanism. For example, it is unknown whether Gly would partially alleviate the reduction in chick weight gain due to excess Keto-Met as demonstrated for Met (17,40).

In these studies, we provide evidence that Keto-Met is highly effective as a source of L-Met and no more growth depressing than L-Met when fed to growing chicks. Implications of this research include potential uses in both human clinical medicine (i.e., nutritional therapy for uremic patients) and production animal agriculture. A Met precursor such as Keto-Met that is not subject to Maillard destruction is viewed as advantageous. Advancements in the efficiency of chemical synthesis may allow Keto-Met to be a viable Met precursor compound in the future.


   FOOTNOTES
 
1 Supported by Degussa, Kennesaw, GA and Ajinomoto, Kawasaki, Japan. Back

2 Author disclosures: R. N. Dilger, C. K. Kobler, C. Weckbecker, D. Hoehler, and D. H. Baker, no conflicts of interest. Back

Manuscript received 24 April 2007. Initial review completed 13 May 2007. Revision accepted 15 May 2007.


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TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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