Why are dietary recommendations for methionine consumption combined with cysteine?

Question

I want to understand the amino acids missing in certain vegetables. I looked up the US recommendations for amino acids (source: wikipedia).

I don’t understand why they pair

• Methionine + Cysteine: 25 mg/g protein
• Phenylalanine + Tyrosine: 47 mg/g protein

I searched for a justification but I cannot find one. While I acknowledge the chemical and structural similarities between them, they are separate amino acids. If these pairs could simply be transformed from one to another, then why bother considering methionine and phenylalanine to be essential? If you could easily convert cysteine to methionine, then methionine could be manufactured by the body. Similarly, so could phenylalanine. But it is commonly assumed this does not occur. Thus, an answer based on the idea that they can be "easily transformed into one another", if true, needs to address these issues.

Here are references for methionine:

The intimate relation between amino acids and protein and nitrogen requirements is well recognized. Nutrition research has focused on the capacity of food to meet the need for nitrogen and indispensable amino acids (IAA) and led to the conclusion that the quality, not just the quantity, of protein is critical. This is especially relevant in regard to the sulfur amino acids (SAA) methionine and cysteine because of the increased understanding of their relation to chronic diseases (e.g., cardiovascular disease, dementia, cirrhosis), immunomodulation, DNA transcription, and RNA translation. Considerable effort has been expended to determine whether and to what extent cysteine can spare the requirement for the IAA methionine. In vivo studies in humans generally concur that the dietary requirement of the SAA ranges between 13 and 16 mg/kg/d, but how much can be met by cysteine relative to methionine remains controversial.

Using the indicator amino acid oxidation (IAAO) approach to further examine this issue, Di Buono et al. (9–11) confirmed the mean requirement for methionine as 12.6 mg/kg/d in the absence of exogenous cysteine but noted that a safe level of intake of total SAA for the population was substantially higher at 21 mg/kg/d.

Naomi K. Fukagawa; Sparing of Methionine Requirements: Evaluation of Human Data Takes Sulfur Amino Acids Beyond Protein, The Journal of Nutrition, Volume 136, Issue 6, 1 June 2006, Pages 1676S–1681S

...and phenylalanine:

Conclusion: On the basis of the 24-h IAAO and 24-h IAAB methods, a mean phenylalanine requirement of 38 mg/kg/d is proposed for healthy well-nourished Indian adults in the absence of tyrosine intake. This finding is similar to that in Western adults.

Anura V Kurpad, Meredith M Regan, Tony DS Raj, Vidya N Rao, Justin Gnanou, Vernon R Young; The daily phenylalanine requirement of healthy Indian adults, The American Journal of Clinical Nutrition, Volume 83, Issue 6, 1 June 2006, Pages 1331–1336

Questions:

• Why would amino acid requirements be grouped together?
• If methionine is considered an essential amino acid, wouldn't grouping it with cysteine allow a food high in cysteine to appear as though it is satisfying your methionine requirement?
• Suppose I consume 12.6 mg/kg/d of methionine, would this affect my ability to consume cysteine?
• If the recommended level of methionine and cysteine is 19 mg/kg/d and this article proposes 12.6 mg/kg/d, then is it logical to consume approximately 6.4mg/kg/d of cysteine?
• If true, would the same logic apply to phenylalanine and tyrosine?

Answer 1

In humans, cysteine can be synthesized from methionine and tyrosine from phenylalanine (note that the reverse pathways do not occur). Because their synthesis requires essential amino acids and the biosynthetic capacity of the organism does not always meet its need, they have been labelled conditionally essential. Under normal circumstances, an adult human can live with no dietary source of cysteine so long as dietary methionine is adequately supplied since the dietary deficiency can be compensated for by biosynthesis. Because of this, though, less dietary methionine is required when the diet is also supplemented with cysteine since less methionine is required to synthesize cysteine. This effect is known as cysteine sparing and a similar effect is observed with tyrosine/phenylalanine.

The data you cite are the reference values for PDCAAS, which is an indicative tool to evaluate the essential amino acid composition of protein sources. This system was introduced in 1991 by the WHO, and in this report they give the following rationale for their combined scoring of methionine and cysteine as sulfur amino acids:

The total of methionine and cystine [is] used for scoring purposes... Cystine is not an essential amino acid but can be synthesized from methionine. Cystine in a diet can thus "spare" methionine, and the total of the two has been found more satisfactory for scoring purposes than methionine alone.

They also recognize and somewhat address the weakness in this methodology that inspired your question:

While it is known that cystine can spare part of the requirement for methionine, FAO/WHO/UNU 1985 does not give any indication of the proportion of total sulphur amino acids which can be met by cystine. For the rat, chick and pig, the proportion is about 50%. Most animal proteins are low in cystine; in contrast, many vegetable proteins, especially the legumes, contain substantially more cystine than methionine. Thus, for animal protein diets or mixed diets containing animal protein, cystine is unlikely to contribute more than 50% of the total sulphur amino acids and scores calculated using cystine plus methionine will be appropriate. However, in certain all vegetable combinations, e.g. wheat and legumes, part of the cystine value may not be realized. Because of insufficient data on human requirements, however, the total of the two sulphur amino acids should, for the present, remain the recommended approach for computing amino acid scores.

...

A further complication arises from our lack of knowledge of the proportion of the total sulphur amino acid requirement which can be met by cystine. Without that knowledge, expression of protein values in terms of the sum total of methionine and cystine has both theoretical and practical limitations.

Answer 2

It's because of their structural similarity. Here are some quick pics of the molecules:

Phenylalanine:

Compare with tyrosine:

You can see that the only difference is the methyl group in para position on the benzyl group in the tyrosine.

Similarly, take a look at cysteine and methionine:

Cysteine:

Compare with methionine:

These two look somewhat less similar; you have an extra methyl group on the methionine, a butyl chain instead of a propyl chain, and the alpha carbon bearing the amino group is in R position instead of S. Nonetheless, they are the only amino acids bearing sulfur Also, if you go back to the original paper, they say,

While RDAs are provided for each age group for the nine indispensable amino acids, histidine, isoleucine, leucine, lysine, sulfur amino acids (methionine + cysteine), aromatic amino acids (phenylalanine + tyrosine), threonine, tryptophan, and valine, the requirements for these amino acids are used to develop the FNB/IOM Protein Scoring Pattern.

Because of their similarities, some of them can be fairly easily transformed one from the one to the other in the body. For instance, cysteine can be produced from L-methionine. This results in it being easier to classify them together, since if they can be produced one from another, they become virtually indistinguishable between the intake and usage pathways.

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Sources:

• Trumbo, Paula, Sandra Schlicker, Allison A. Yates, and Mary Poos. "Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. (Commentary)." Journal of the American Dietetic Association 102, no. 11 (2002): 1621+.

• Institute of Medicine of the National Academies. 2003. Dietary Reference Intakes. p. 138.

• U.S. National Library of Medicine. Toxicology Data Network: HSDB: (L)-Tryptophan.

• Bin P, Huang R, Zhou X. 2017. Oxidation resistance of the sulfur amino acids: Methionine and cysteine. BioMed Research International 2017 : 9584932-6.