BIOINORGANIC CHEMISTRY A Short Course Second Edition

328 GROUP I AND II METALS IN BIOLOGICAL SYSTEMS: GROUP II

membrane contains high levels of Ca 2+ - ATPase. With the action of Ca 2+ -

ATPase, the SR releases calcium ions into the sarcoplasm to initiate

muscle contraction, and it releases the calcium ions into the lumen during

relaxation.

The Ca 2+ - ATPase from fast - twitch rabbit skeletal muscle sarcoplasmic
reticulum (SERCA1a) is a large membrane protein of 110 kDa that has more
than 990 amino acid residues. The enzyme actively transports two Ca 2+ ions
per ATP hydrolyzed across the membrane from the cytoplasm to the lumen
against a concentration gradient. At the same time, two to three protons are
transported in the opposite direction. Activity of Ca 2+ - ATPase is crucial to
skeletal muscle function. The reaction cycle, adapted from reference 96 , pro-
ceeds from the upper left in Figure 6.28 as the high - affi nity form of the enzyme,
E 1 , receives two moles of calcium ion from the cytoplasm (where Ca 2+ concen-
tration has become unacceptably high) and releases 2 – 3 protons to the cyto-
plasm. ATP complexed with Mg 2+ ions enters and is bound to the enzyme at
a specifi c location. The enzyme is then phosporylated at a specifi c residue,
asp351 (D351) as energy is imparted to the system through an ATP → ADP
hydrolysis. In the next step, ADP is released. Continuation of the cycle causes
calcium ions to be released to the lumen as 2 – 3 protons enter from the lumen.
Phosphate ion is released along with magnesium ions to form the low affi nity
E 2 state. Transformation of the enzyme ’ s low - affi nity state to its high - affi nity
state restarts the cycle. Figure 6.28 indicates the Protein Data Bank accession
numbers for the known X - ray crystallographic structures corresponding to the
various cycle intermediates.

Figure 6.28 The Ca 2+ - ATPase reaction cycle. (Adapted by permission from Macmillan
Publishers Ltd from Figure 1 of reference 96 , copyright 2004.)

E 1

E 2

Ca 2 E 1

E 2 .Pi

2 Ca2+

cytoplasm

Ca 2 E 1 .ATP

Ca 2 E 1 P.ADP

PDB: 1T5T, 1WPE

Ca 2 E 1 P

2 - 3 H+ lumen

2 Ca2+ lumen

E 2 P

Pi

2 - 3 H+

cytoplasm

Mg2+

Mg2+

PDB: 1WPG

ATP

ADP

PDB: 1SU4 PDB: 1T5S, 1VFP

PDB: 1XP5

PDB: 1IWO