Metabolic Biochemistry BIBC 102

1
Metabolic BiochemistryBIBC 102

• Lecture 22
• November 28, 2007

2
C14 fatty acid
7 acetyl CoA 6 rounds of b
oxidation
3
b-oxidation takes place in the matrix
ofmitochondria
LNC 17-7
4
first oxidation/reduction with membrane-bound enzy
me and FAD ? FADH2
second oxidation/reduction with soluble enzyme
and NAD ? NADH
LNC 19-8
5
How to deal with unsaturated fatty acids
cis D3 - or double bond between b-g
LNC 17-9
6
LNC 17-10
7
How to deal with a fatty acid containing
an uneven number of carbons
C3
C4
LNC 17-11
8
LNC box 17-1
9
Co at 25/lb your body probably contains
0.000..1 cents worth of essential cobalt
LNC box 17-2
10
(No Transcript)
11
Cobalamin - vitamin B12
12
Vitamin B12 (cobalamin) is an important
water-soluble vitamin. In contrast to other
water-soluble vitamins it is not excreted quickly
in the urine, but rather accumulates and is
stored in the liver, kidney and other body
tissues. As a result, a vitamin B12 deficiency
may not manifest itself until after 5 or 6 years
of a diet supplying inadequate amounts. Vitamin
B12 functions as a methyl donor and works with
folic acid in the synthesis of DNA and red blood
cells and is vitally important in maintaining the
health of the insulation sheath (myelin sheath)
that surrounds nerve cells. The classical vitamin
B12 deficiency disease is pernicious anaemia, a
serious disease characterized by large, immature
red blood cells. It is now clear though, that a
vitamin B12 deficiency can have serious
consequences long before anaemia is evident. The
normal blood level of vitamin B12 ranges between
200 and 600 picogram/milliliter (148-443
picomol/liter). Although deficiency is far more
common than excess when it comes to vitamin B12
status cases have been reported where blood
levels exceeded 3000 picograms/milliliter. Such
high levels may be caused by bacterial overgrowth
as outlined in the article Vitamin B-12 Overload
A deficiency often manifests itself first in the
development of neurological dysfunction that is
almost indistinguishable from senile dementia and
Alzheimer's disease. There is little question
that many patients exhibiting symptoms of
Alzheimer's actually suffer from a vitamin B12
deficiency. Their symptoms are totally reversible
through effective supplementation. A low level of
vitamin B12 has also been associated with asthma,
depression, AIDS, multiple sclerosis, tinnitus,
diabetic neuropathy and low sperm counts.
Clearly, it is very important to maintain
adequate body stores of this crucial vitamin.
The amount of vitamin B12 actually needed by the
body is very small, probably only about 2
micrograms or 2 millionth of a gram/day.
Unfortunately, vitamin B12 is not absorbed very
well so much larger amounts need to be supplied
through the diet or supplementation. The richest
dietary sources of vitamin B12 are liver,
especially lamb's liver, and kidneys. Eggs,
cheese and some species of fish also supply small
amounts, but vegetables and fruits are very poor
sources. Several surveys have shown that most
strict, long-term vegetarians are vitamin B12
deficient. Many elderly people are also deficient
because their production of the intrinsic factor
needed to absorb the vitamin from the small
intestine decline rapidly with age. Fortunately,
oral supplementation with vitamin B12 is safe,
efficient and inexpensive. Most multi-vitamin
pills contain 100-200 microgram of the
cyanocobalamin form of B-12. This must be
converted to methylcobalamin or adenosylcobalamin
before it can be used by the body. The actual
absorption of B12 is also a problem with
supplements. Swallowing 500 micrograms of
cyanocobalamin can result in absorption of as
little as 1.8 microgram so most multivitamins do
not provide an adequate daily intake. The best
approach is to dissolve a sublingual tablet of
methylcobalamin (1000 micrograms) under the
tongue every day. That will be sufficient to
maintain adequate body stores. However, if a
deficiency is actually present then 2000
microgram/day for one month is recommended
followed by 1000 microgram/day. Some physicians
still maintain that monthly injections of vitamin
B12 is required to maintain adequate levels in
the elderly and in patients with a diagnosed
deficiency. There is however, no scientific
evidence supporting the notion that injections
are more effective than sublingual
supplementation.
13
Degradation of very long chain fatty acids in the
peroxisome
catalase
LNC 17-12
14
A deficiency in peroxisomal acyl-CoA synthetase
causes X-adrenoleukodystrophy (X-ALD) made
famous by the movie Lorenzos Oil Long chain
fatty acids accumulate in the blood and
destroythe myelin sheath
15
X-ALD
16
Lorenzos Oil
17
Plants can convert fatty acids toglucose(in
certain tissueswith glyoxisomes)
Glyoxalate Cycle in Plants
LNC 17-13
18
Animals/humans cannot convert fatty acids to
glucoseacetyl-CoA cannot be converted to a
three- or four-carbon intermediate to make PEP
for gluconeogenesis
When glucose is depleted due to starvation or due
to some pathological conditions (diabetes),
fatty acids are metabolized to ketone
bodies They are small molecules, soluble in
water/blood, and can get through biological
membranes (the blood-brain barrier) to serve as
fuel forsustaining essential neurological
processes
19
Ketone Bodies
20
Conditions favoring ketone body
formation depletion of OA for
gluconeogenesis acetyl-CoA becomes available
for ketone body synthesis
LNC Fig 17-18
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
(No Transcript)
25
(No Transcript)
26
HMG-CoA
Ketone bodies
Cholesterol
27
Fatty Acid Synthesis
LNC Chapter 21
28
acetyl-CoA CO2 gt malonyl-CoA
the enzyme has three functional regions -
biotin carrier protein - biotin carboxylase -
transcarboxylase
LNC Fig. 21-1
29
End of Lecture 21 November 28, 2007
30
LNC Fig. 21-4
31
acyl carrier protein
LNC Fig. 21-2
32
LNC Fig. 21-2
33
LNC Fig. 21-2
34
This group is transferred to the other SH group
to free the ACP-SH for the next malonyl group
LNC Fig. 21-2
35
beginning of the second round
LNC Fig. 21-6
36
LNC Fig. 21-3
37
(No Transcript)
38
Fig. 1. Catalytic cycle and domain organization
T. Maier et al., Science 311, 1258 -1262
(2006)
Published by AAAS
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
LNC Fig. 21-5
43
LNC Fig. 21-5
44
LNC Fig. 21-5
45
LNC Fig. 21-5
46
LNC Fig. 21-5
47
LNC Fig. 21-5
48
LNC Fig. 21-5
49
LNC Fig. 21-5
50
LNC Fig. 21-7
51
The normal product of fatty acid synthase is
palmitate (16 carbons) elongation to stearate
and longer chains takes place in the
endoplasmic reticulum (ER) desaturation to
oleate also occurs in the ER poly-unsaturated t
he shaded fatty acids are essential FA for
humans but are made only in plants
LNC Fig. 21-13
52
Desaturation of fatty acids in vertebrates (in
the smooth ER) requires molecular oxygen
53
(No Transcript)
54
(No Transcript)
55
(No Transcript)
56
LNC Fig. 21-8
57
LNC Fig. 21-9
Source of NADPH
Malic enzyme is found in liver and other animal
tissues
A similar enzyme is found in bundle sheath cells
in C4 plants
58
Source of NADPH
59
Source of NADPH
photosynthesis
60
from glucose to fatty acids glucose
pyruvate (in
cytosol) pyruvate acetyl-CoA (in
mitochondria) acetyl-CoA fatty acid (in
cytosol)
How does acetyl-CoA come out of mitochondria ?
61
End of Lecture 23 March 5, 2007