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a DHA co-factor receptor site on rhodopsin that may explain the need for DHA in vision. It is
known that upon complete removal of DHA and its metabolic precursors from the diet,
mammals will ferociously retain ROS DHA at the expense of all other lipids [56] .
D-
-Hydroxybutyrate Dehydrogenase
D-
b
-hydroxybutyrate dehydrogenase is a lipid requiring enzyme that is found on the
inner surface of the inner mitochondrial membrane where it catalyzes the reaction:
b
NAD þ 4
H þ
ð
R
Þ
-
-hydroxybutanoate
þ
acetoacetate
þ
NADH
þ
3
What makes this enzyme so unusual is its absolute specificity for phosphatidylcholine
(PC) [61,62] . When purified free of lipid the enzyme is inactive. Activity is regenerated by
adding PC or lipid mixtures containing PC. The active form of the enzyme is the enzyme-
PC complex. Many membrane enzymes can be functional in bilayers made from PC, but
D-
b
-hydroxybutyrate dehydrogenase is the only one with an absolute requirement for PC.
Cytochrome c Oxidase
Themost logical place to look for an absolute link between a specific lipid and amammalian
function would be cardiolipin (CL) and mitochondrial electron transport and oxidative phos-
phorylation. CLwas first isolated frombeef heart in 1942 [63] and its presencewas soon shown
to be characteristic of bioenergeticmembranes (bacterial plasmamembrane and themitochon-
drial inner membrane). Cytochrome oxidase is the terminal component in electron transport
where its function is to reduce O 2 to H 2 O. CL comprises about 20% of the total lipid composi-
tion of the mitochondrial inner membrane. The structure of CL (see Chapter 5) is clearly the
most unusual of all phospholipids. It is two phosphatidic acids held together by a glycerol.
At physiological pH, its large head group is a di-anion and it has four acyl chains. Due to its
high negative charge density, CL can be induced by Ca 2 þ to undergo a lamellar-to-hexagonal
(L a -H II ) phase transition. An almost limitless number of possible acyl chain combinations
would imply that CL could exist in an enormous number of different molecular species.
However, the vast majority of acyl chains in CL are linoleic acid (18:2 D 9,12 ) with lesser amounts
of oleic acid (18:1 D 9 ) and linolenic acid (18:3 D 9,12,15 ). This severely limits the number of possible
molecular species to a manageable number.
So is CL, with all of its unusual properties, absolutely required for cytochrome oxidase
activity? Are some of the reputed ~40
55 annular lipids required to solvate cytochrome
oxidase bound to specific co-factor sites? A number of reports have linked CL levels and
full electron transport activity, particularly of cytochrome oxidase. In one report, Paradies
exposed rat liver mitochondria to a free radical generating system that peroxidized the CL
[64] . Concomitant with the loss of CL was a decrease in cytochrome oxidase activity.
Lipid-soluble antioxidants prevented the loss of CL and preserved the enzyme activity.
External addition of CL, but not any other phospholipid, prevented the loss of cytochrome
oxidase activity. This experiment demonstrated a close correlation between oxidative
damage to CL and reduced cytochrome oxidase activity. In a related study these same inves-
tigators also demonstrated that lower cytochrome c oxidase activity observed in heart mito-
chondria from aged rats can be fully restored to the level of young control rats by
exogenously-added CL [65] . Other mitochondrial diseases (e.g. Tangier disease and Barth
syndrome) have also been linked to CL and can be treated by controlling CL levels.
e
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