How many amino acids are in hemoglobin?
Chain lengths, hemoglobin types and the full sequences
Matic Broz, PhD6 min
Adult hemoglobin A, the protein that carries oxygen in red blood cells, contains 574 amino acids. They are divided among four separate protein chains: two alpha chains of 141 amino acids each and two beta chains of 146 each, so 2 × 141 + 2 × 146 = 574.
The same total holds for fetal hemoglobin, the minor adult form HbA2 and the hemoglobins of the early embryo, because each pairs two alpha-like chains of 141 residues with two beta-like chains of 146. Counts of 578, 142 and 147 come from sequence databases that include the methionine every chain starts with before the cell trims it off.
How many amino acids are in hemoglobin?
One molecule of adult human hemoglobin A has 574 amino acid residues divided among four globin chains.[1][2][3] A residue is one amino acid as it sits in a protein chain, so the count measures length, not the number of amino acid types; that separate question is how many amino acids exist.
Hemoglobin A is a tetramer, written α2β2: two alpha chains contribute 282 residues and two beta chains contribute 292. The four chains are not joined by peptide bonds. They hold together through contacts between their surfaces, which is why the 574 describes an assembled complex rather than one long polypeptide. The deoxyhemoglobin crystal structure 4HHB shows exactly this arrangement, with alpha chains A and C at 141 residues and beta chains B and D at 146.[4]
Each chain also carries one heme group, the iron-containing ring that binds oxygen, so a hemoglobin molecule holds four hemes and up to four oxygen molecules.[3] Heme is not an amino acid and is not part of the 574.
At 141 and 146 residues, the globin chains are short proteins, well under the roughly 375-residue median human protein. Myoglobin, hemoglobin's single-chain relative that stores oxygen in muscle, has 153 residues, about the length of one hemoglobin chain.[5]
How many amino acids are in the alpha and beta chains?
The mature human alpha chain contains 141 amino acid residues and the mature beta chain contains 146.[1][2][3] Two genes, HBA1 and HBA2, encode an identical alpha protein, while HBB encodes beta.[1][2] The two chains are similar in length and fold, but their sequences differ at most positions.
These are the mature sequences, in one-letter amino acid code, as UniProt records them with the starting methionine removed. Position 1 is the first letter of each line, the numbering hemoglobin researchers use.
Alpha chain (141 residues)
VLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGHGKKVADALTNAVAHVDDMPNALSALSDLHAHKLRVDPVNFKLLSHCLLVTLAAHLPAEFTPAVHASLDKFLASVSTVLTSKYR
Beta chain (146 residues)
VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYHThe same chains can be pulled from the 4HHB coordinates with PDB to FASTA, which returns four sequences, one per chain, because the structure contains two copies of each.
Do fetal and other hemoglobins have 574 amino acids too?
Yes. Every normal human hemoglobin combines two alpha-like chains with two beta-like chains, and all the alpha-like chains are 141 residues long while all the beta-like chains are 146.[1][2][6][7][8][9][10] The total is therefore 574 whichever pair a red blood cell is making.
What changes over a lifetime is which genes are switched on. In the early embryo, zeta (ζ) and epsilon (ε) chains form hemoglobins Gower 1, Gower 2 and Portland. Fetal hemoglobin, α2γ2, then dominates the last two trimesters of pregnancy, and by the end of the first year of life the adult pattern has taken over. In healthy adults, hemoglobin A makes up about 97% of the total, HbA2 about 2% and fetal hemoglobin about 1%.[11]
| Hemoglobin | Chains | Residues per chain | When it is made | Total residues |
|---|---|---|---|---|
| HbA | α2β2 | 141 and 146 | Adults, about 97% of hemoglobin | 574 |
| HbA2 | α2δ2 | 141 and 146 | Adults, about 2% of hemoglobin | 574 |
| HbF (fetal) | α2γ2 | 141 and 146 | Fetus and newborn; about 1% in adults | 574 |
| Gower 1 | ζ2ε2 | 141 and 146 | Early embryo | 574 |
| Gower 2 | α2ε2 | 141 and 146 | Early embryo | 574 |
| Portland | ζ2γ2 | 141 and 146 | Early embryo | 574 |
Equal length does not mean equal sequence. Comparing the UniProt sequences position by position, we find that the delta chain of HbA2 differs from beta at 10 of its 146 positions and the gamma chain of fetal hemoglobin at 39.[2][6][8] Fetal hemoglobin itself comes in two forms, named Gγ and Aγ for the glycine or alanine at gamma position 136; the two are functionally identical.[11]
The exceptions are abnormal hemoglobins that form when alpha chains are missing. In severe alpha thalassemia, spare gamma chains assemble into hemoglobin Bart's, a tetramer of four gamma chains with 4 × 146 = 584 residues that lacks the cooperative oxygen binding of normal hemoglobin.[7]
Which amino acids are in hemoglobin?
Hemoglobin A contains 19 of the 20 standard amino acids. Counting each residue in the mature UniProt sequences, we find no isoleucine in either chain, while leucine and alanine are the most frequent, with 72 copies each in the tetramer.[1][2] Table 2 lists the full composition.
| Amino acid | Alpha chain | Beta chain | Hemoglobin A |
|---|---|---|---|
| Alanine (A) | 21 | 15 | 72 |
| Leucine (L) | 18 | 18 | 72 |
| Valine (V) | 13 | 18 | 62 |
| Lysine (K) | 11 | 11 | 44 |
| Glycine (G) | 7 | 13 | 40 |
| Histidine (H) | 10 | 9 | 38 |
| Serine (S) | 11 | 5 | 32 |
| Threonine (T) | 9 | 7 | 32 |
| Aspartic acid (D) | 8 | 7 | 30 |
| Phenylalanine (F) | 7 | 8 | 30 |
| Proline (P) | 7 | 7 | 28 |
| Glutamic acid (E) | 4 | 8 | 24 |
| Asparagine (N) | 4 | 6 | 20 |
| Arginine (R) | 3 | 3 | 12 |
| Tyrosine (Y) | 3 | 3 | 12 |
| Glutamine (Q) | 1 | 3 | 8 |
| Cysteine (C) | 1 | 2 | 6 |
| Methionine (M) | 2 | 1 | 6 |
| Tryptophan (W) | 1 | 2 | 6 |
| Isoleucine (I) | 0 | 0 | 0 |
| Total | 141 | 146 | 574 |
The same counts come out of amino acid composition when either sequence above is pasted in. A sequence copied straight from a database will return 142 or 147 residues and one extra methionine, for the reason explained next.
Why do some sources report 578 amino acids?
The higher counts include the initiator methionine, the amino acid every protein chain starts with when it is first made. UniProt stores the full translated alpha sequence at 142 amino acids and beta at 147, and in both entries marks that first methionine as removed from the mature protein.[1][2] Four removed methionines are the whole difference between the two totals:
2 × 142 + 2 × 147 = 578 translated residues
2 × 141 + 2 × 146 = 574 mature residues
The offset matters most for sickle cell disease. Sickle hemoglobin carries valine instead of glutamic acid at the sixth position of the beta chain, the change known as β6 Glu→Val.[3] In UniProt and in genetic variant notation, which count the methionine as position 1, the same change sits at position 7 and is written Glu7Val. Hemoglobins C and E follow the same pattern: lysine at beta position 6 and 26 in the hemoglobin literature, or 7 and 27 in the database.[2]
Whichever convention a source uses, the protein is the same. Adult hemoglobin carries 574 amino acids in its working form, and every other normal human hemoglobin matches that total even though the chains it is built from change from embryo to adult.
