Anabolism:
synthesis
Catabolism:
degradation
Where does Fatty acid Beta oxidation occurs?
Peroxisome and Mitochondria
What is denoted by "saturated" and "unsaturated" fatty acids?
The absence of double bonds (saturated) and The presence of double bonds (unsaturated)
Naturally occurring Fatty acids usually assume the ___ configuration.
Cis
The two prerequisite steps that precede Beta oxidation:
(i) ACTIVATION of fatty acyl chain (C8-C20), and (ii) TRANSPORT of the activated fatty acyl chain into the mitochondria.
ACS (Acyl-CoA Synthesthase)
Used to activate FA anabolism; This rxn requires ATP hydrolysis to drive the formation of acyl-CoA.
Where are the various locations for ACS?
In the MITOCHONDRIA MATRIX (shorter chain FA, <C8); the OUTER MITOCHONDRIAL MEMBRANE (longer chain FA, C8-C20); the PEROXISOME LUMEN (very long FA, >C20) and on the PERSOXISOME SURFACE (long chain FA ~C16-C20)
Energy required to activate a fatty acid molecule:
2 high energy bonds are required
= 2 ATP equivalent
There are at least ___ different ACS exists that are responsible for acyl-CoA formation related to mitochondrial B oxidation
FIVE: 3 of the ACSs act on short chain FAs, whereas 2 ACSs act on longer chain FA [ in the mitochondria].
Acyl-Carnitine
Formed in the cytosol from the condensation of acyl-CoA to carnitine, catalyzed by CPT. Important intermediate for transferring Acyl-CoA into the mitochondrial matrix; The committing step in Beta Oxidation
CPT (Carnitine Palmitoyltransferase)
Two types: CPT1 (located on the outer mitochondrial membrane) and CPT2 (located on the inner mitochondrial membrane). Multiple forms present in different cell types: Liver (CPT1A); Muslce, brown-adipose tissue, heart (CPT1B); brain (CPT1C)
Fatty Acyl-CoA
Important substrate in B-oxidation; Formed in the cytosol, It is not premeable to the mitochondrial matrix, thus must be converted to Acyl-Carnitine and transported into matrix via protein carrier.
Transportase
Protein Carrier; transports acyl-carnitine from cytosol to mitochondrial matrix as well as transports carnitine from mitochondrial matrix to cytosol.
formation of acyl-carnitine, catalyzed by ___, on the ____ of mitochondrion
CPT1, outer membrane
Carnitine
Used in the formation of acyl-CoA (prerequisite step in B-oxidation); Condenses with FA in a rxn catalyzed by ACS
acyl-carnitine is converted back to acyl-CoA, catalyzed by ___ on the matrix side of ____ of mitochondrion
CPT2, inner membrane
The B oxidation pathway is composed of these four rxns?
(i) first dehydrogenation between alpha-beta bond (ii) hydration of the alpha-beta double bond, (iii) second dehydrogenation resulting in Beta-ketone (thus the name of B oxidation), and (iv) cleavage between alpha-beta bond [The last reaction results in a
Each round of B oxidation yields...
(1) acetyl-CoA, (1) FADH2, and (1) NADH; all of which can be utilized for ATP generation through oxidative phosphorylation.
Acyl-CoA dehydrogenase (AD)
Catalyzes the 1st step in B-Oxidation: the conversion of fatty acyl-CoA into trans-delta2-enoyl-CoA. (FAD-dependent) Note: different AD used for different chain lengths (i.e. VLCAD (for very long chain acyl-CoA), LCAD (for long chain), MCAD (for medium ch
MCAD
The MCAD is a tetramer that is composed of four identical subunits; each subunit contains a FAD molecule. Deficiency of MCAD in humans has profound pathologic impact on infant development.
Enoyl-CoA hydratase (EH)
Catalyzes the hydration reaction of trans enoyl-CoA. This enzyme is STEREOSPECIFIC (it only acts on trans alpha=beta configuration)
Hydroxyacyl-CoA dehydrogenase (HAD)
(NAD+-dependent); catalyzes the formation of B-ketoacyl-CoA
B-ketoacyl-CoA thiolase (KT)
The thiolase catalyzed reaction is reversible; results in the fatty acyl-CoA that is 2 atoms shorter
For long chain FAs (B-oxidation process), ______ ezymatic activities reside in one____ (a4b4) trifunctional protein in mitochondria
the EH, HAD and KT; octameric
For short and medium chain acyl-CoA, B oxidation process, the EH, HAD and KT activities are encoded by ____ enzyme molecules.
separate
What is Beta Oxidation?
The degradation of unsaturated fatty acids
What are the two problems associated with B oxidation of unsaturated fatty acids?
(i) spacial hinderance by cis Beta (C2)-Gamma (C3) double bond, and (ii) delta4 double bond; [ Position delta 9 in oleic acid or linoelic acid prevents hydration rxn by EH, which can only recognize a=B double bonds; and in the case of lineolic acid, the o
How are the problems associated with B oxidation fixed?
(i) reacting Enoyl-CoA isomerase, (ii) converting 2,4 di-enoyl to 3-enoyl by NADPH-dependent di-enyol-CoA reductase, and isomerizing it to 2-enoyl-coA by an isomerase rxn. The 2-enoyl-CoA contains the a=b double bond that is recognizable by EH.
Peroxisomes:
subcellular organelle for B-oxidation of fatty acids (aka "Microbodies"); function in shortening long chain fatty acids
Hydrogen Peroxide (H2O2)
Often generated by the first reaction of B-oxidation in the peroxisome (FADH2 reacts with O2 to from H2O2)
What does peroxisomes do?
possess enzymes involved in beta oxidation;
Why doesn't B-oxidation in the peroxisome generate a lot of energy?
the ELECTRON TRANSPORT SYSTEM for generation of ATP through oxidative phosphorylation, thus B- oxidation of fatty acids in peroxisomes does not generate much energy
what happens to FADH2, NADH, and acetyl-CoA generated in the peroxisomes?
FADH2 molecules generated in peroxisomes are converted into H2O2 and not utilized for ATP generation. NADH and acetyl-CoA generated in peroxisomes are transported to mitochondria for energy production.
Zellweger syndrome biogensis disorders
deficiency in peroxisome biosynthesis (biogensis disorders)
Why study Peroxisome?
good target for treatment of insulin resistance type 2 diabetes; FIBRATES effective fro treatment of hypercholesterterolemia
Fibrates
group of compounds that have been found to induce peroxisome proliferation, thus enhance B-oxidation
peroxisome proliferator-activated receptor (PPAR)
proteins in cells; transcription factors that mediate expression of genes involved in peroxisome proliferation
PPAR ligands
interact with PPAR and are antidiabetic agents (e.g. Rosiglitazone and Pioglitazone); these ligands are Thiazolidinediones
ketogenesis
a process that occurs during starvation; the adipose tissue releases fatty acid into the blood stream, which is transported into muscle for energy (B oxidation) and into the liver
How are "ketone bodies" generated
The liver has a set of enzymes that can convert acetyl-CoA (generated from B oxidation) to ketone bodies [This happens under conditions where fatty acid B oxidation becomes a major source for energy (e.g. during starvation)]
Ketone Bodies
acetoacetate, B-hydroxybutyrate, and acetone
What do ketone bodies do?
produced in the liver when carbohydrate supply is low (e.g. fat rich diet or starvation); used as a major source of energy under these conditions
hyperketonemia (ketoacidosis)
is common in diabetes; results from excessive ketogenesis which results in acidification of the blood.
Neonatal Adrenoleukodystrophy
deficiency in the transport protein for importing long chain FAs into peroxisome-->Those with peroxisome diseases suffer from neurological disorders as a consequence of abnormal fatty acid catabolism.
Acetoacetate
Generated from B-Oxidation; A ketone body and a usesful intermediate for the formation of the other two ketone bodies: B-hydroxybutyrate, and acetone
B-hydroxylbutyrate
Ketone body; generated from the acetoacetate in a rxn catalyzed by B-hydroxylbutyrate dehydrogenase
Acetone
Ketone body; generated from the spontaneous decarbosylation of acetoacetate.