A Plausible Entry to 20 Proteinogenic Amino Acids via Aminomalononitrile Derivatives

Dear Editor,

It is not yet known why the number of proteinogenic amino acids is limited to 20. Some explanations for this problem have been attempted, but it is still unresolved.^1,2 Aminomalononitrile is a hydrogen cyanide (HCN) trimer and its alkylation is a possible route to amino acids under prebiotic conditions (Scheme 1). Thanassi ³ obtained Thr and Glu by this route. We recently reported a model study to Phe, albeit under nonprebiotic conditions. ⁴ Some basic structural features of proteinogenic amino acids could be explained; namely, (i) all are α-amino acids, (ii) all have one hydrogen atom attached to the α-carbon, (iii) all four aromatic amino acids (Phe, Tyr, His, and Trp) have one methylene between the aromatic ring and the α-carbon, and (iv) Pro has a sec-amino group. ⁴

Scheme 1.

Formation of amino acids by alkylation of aminomalononitrile.

Here we propose an analogous route shown in Scheme 2. The difference between Schemes 1 and 2 is only the entry order of the alkylating compound and HCN molecules, but Scheme 2 is more suitable than Scheme 1 in the explanation of 20 side chains. The side-chain precursors are listed in Table 1.

Scheme 2.

Formation of amino acids from nitrile compounds.

Table 1.

Side-Chain Precursors for Proteinogenic Amino Acids. ^a

Amino acid	Precursor	Amino acid	Precursor
	Alkenes		Allylic/benzylic compounds
Val	CH2 = CHMe	Pro	CH2 = CHCH2X b
Ile	MeCH = CHMe, CH2 = CHEt	Phe	1 b
Leu	CH2 = CMe2	Tyr	2 b
	Aldehydes	His	3 b
Ser	HCHO	Trp	4 b
Thr	MeCHO		Others
	Cyclic amine/guanidine	Cys	CH2 = S
Lys	Pyrrolidine	Gln, Glu	CH2 = CHCN c  + HCN
Arg	5	Met (R = Me) Hcy (R = H)	CH2 = CHCN c  + RSH

^a

Precursors of Gly, Ala, Asn, and Asp are not listed. Gly, Ala, and Asp are obtained from HCN/H₂O under various conditions.^5-8 Asn is a derivative of Asp. In Scheme 2, precursors for Ala and Asn/Asp are MeCN and NCCH₂CN (or XCH₂CN), respectively.

^b

X = leaving group.

^c

Acrylonitrile is an adduct of acetylene and HCN.

The first reaction directed to Val, Ile, Leu, Ser, and Thr is not substitution but the addition of HCN to alkenes or aldehydes. Other simple compounds such as alkylamines, alcohols, and carboxylic acids were not chosen as the side-chain precursors due to low reactivity in Scheme 2 reaction. Precursors of Phe, Tyr, His, Trp, Arg, Lys, and Cys are either relatively complex or rare molecules. We believe that these amino acids have been incorporated into proteinogenic members in the peptide formation stage. Their advantages are a hydrophobic effect (Phe, Tyr, and Trp), H⁺-transfer from amino group to basic side-chain (His, Arg, and Lys), and native chemical ligation ⁹ (Cys). We speculate that Met was originally Hcy (homocysteine). The reaction of Hcy-thiolactone with another amino acid is the first step of peptide formation. Probably, Met is a capped Hcy whose role has been transferred to the start codon.

In addition to the above-mentioned (i) – (iv), more structural features of proteinogenic amino acids can be rationalized; namely, (v) Lys has four methylenes (pyrrolidine is the smallest stable cyclic amine), (vi) Arg has three methylenes (5 is the smallest stable cyclic guanidine), (vii) 2-aminobutanoic acid is not a member (its precursor, ethylene, is less reactive than alkylated alkenes), (viii) linear hydrocarbon chains are absent (norvaline and norleucine are anti-Markovnikov products, while Val and Ile are Markovnikov products), and (ix) structurally similar amino acids are present (different precursors). Several nonproteinogenic amino acids including 2-aminobutanoic acid and β-alanine are often found in various simulated experimental products and meteorites.^10,11

Unfortunately, there is no experimental evidence for this scheme as most reactions are expected to be too slow to be detected on laboratory timescales. We believe that Scheme 2 and Table 1 explain the origin of the 20 side chains, but some other skeletal structures, including high-molecular-weight complex amino acid precursor, ¹¹ are possible in place of the aminomalononitrile body. The origin of precursor compounds given in Table 1 is not clear yet. However, some simple hydrocarbons ¹² and aromatic compounds ¹³ have been obtained from inorganic gases in simulated high-energy experiments. Further studies are needed.