~Teachingcenter的醫學筆記~

人類血紅素基因的誤義突變
Missense Mutations in Human Hemoglobin

Sickling (鐮狀)

1. Residue changed：β6 (A3)
   • Changed：Glu → Val
   • Name：S
   • Consequences of mutation：Sickling
   • Explanation：Val fits into EF pocket in chain of another hemoglobin molecule.
     ※ Polymerization of sickle cell hemoglobin is driven by exposure of hydrophobic residues. The “EF corner” (of the E helix and F helix), exposed in the deoxy state, includes residues F85 and L88, which form a hydrophobic pocket sometimes called the “EF corner pocket”.
2. Residue changed：β6 (A3)
   • Changed：Glu → Ala
   • Name：G Makassar
   • Consequences of mutation：Not significant
   • Explanation：Ala probably does not fit the pocket as well.
3. Residue changed：β121 (GH4)
   • Changed：Glu → Lys
   • Name：O Arab, Egypt
   • Consequences of mutation：Enhances sickling in S/O heterozygote (sickle/O Arab heterozygote)
   • Explanation：β121 lies close to residue β6; Lys increases interaction between molecules.

Change in O2 affinity (對氧親和力改變)

1. Residue changed：α87 (F8)
   • Changed：His → Tyr
   • Name：M Iwate
   • Consequences of mutation：Forms methemoglobin, decreased O₂ affinity
   • Explanation：The His normally ligated to Fe has been replaced by Tyr.
2. Residue changed：α141 (HC3)
   • Changed：Arg → His
   • Name：Suresnes
   • Consequences of mutation：Increases O₂ affinity by favoring R state
   • Explanation：Replacement eliminates bond between Arg 141 and Asn 126 in deoxy state.
3. Residue changed：β74 (E18)
   • Changed：Gly → Asp
   • Name：Shepherds Bush
   • Consequences of mutation：Increases O₂ affinity by decrease in BPG binding
   • Explanation：The negative charge at this point decreases BPG binding.
4. Residue changed：β146 (HC3)
   • Changed：His → Asp
   • Name：Hiroshima
   • Consequences of mutation：Increases O₂ affinity, reduced Bohr effect
   • Explanation：Disrupts salt bridge in deoxy state and removes a His that binds a Bohr effect proton.

Heme loss (血基質喪失、不帶有血基質)

1. Residue changed：β92 (F8)
   • Changed：His → Gln
   • Name：St. Etienne
   • Consequences of mutation：Loss of heme
   • Explanation：The normal bond from F8 to Fe is lost, and the polar glutamine tends to open the heme pocket.
2. Residue changed：β42 (CD1)
   • Changed：Phe → Ser
   • Name：Hammermith
   • Consequences of mutation：Unstable, loses heme
   • Explanation：Replacement of hydrophobic Phe with Ser attracts water into heme pocket.

Dissociation of tetramer (血紅素四合體解離)

1. Residue changed：α95 (G2)
   • Changed：Pro → Arg
   • Name：St. Lukes
   • Consequences of mutation：Dissociation
   • Explanation：Chain geometry is altered in subunit contact region.
2. Residue changed：α136 (H19)
   • Changed：Leu → Pro
   • Name：Bibba
   • Consequences of mutation：Dissociation
   • Explanation：Pro interrupts helix H.