Fatty Acids Flashcards
where does the acetyl CoA for fatty acid synthesis come from?
primarily from catabolism of carbohydrates
the three inputs into the acetyl CoA pool
- carbohydrates
- fatty acids
- amino acids
essential features of fatty acid
methyl terminus (omega end)
linear unbranched alkyl chain
even # of Cs
carboxylic acid group (#1)
saturated - MUFA (one double bond),PUFA (2)
of carbons in small, med, lrg, FA
Small 2-4
Medium 6-12
Long 14-20 Carbons
Very long
18:2delta9,12
18 carbons
2 double bonds at positions 9 and 12
9,12-octadecadienoic acid
families of fatty acids
(n-reference = omega-reference)
n = # of carbons
n-6;
18-6 = first double bond is 12 C in from the carboxylic end or methyl terminus
double bonds are generally ___ C apart
3 carbons apart
fatty acids used for;
- triglyceride synthesis
- cholesterol esters
- phospholipids, glycosolipids
- eicosanoid hormones
synthesis of FA is located in….
degradation of FA is located in…
synthesis of FA = cytosol
degradation of FA = mitochondria
(of certain tissues)
tissues of fatty acid synthesis
primary ; liver cytosol adipose CNS lactating mammary gland (all cytosol)
reactants and product of FA synthesis
8 acetyl-CoA
7 ATP
14 NDAPH
endergonic, reductive reactions
primary product; palmate
where do all the C for palmitate come from?
acetyl CoA;
from glucose (via glycolysis)
from pyruvate -> acetyle CoA (PDH)
source of NADPH for FA synth
phentose phosphate pathway, primarily
how does acetyl CoA get into the cytosol
can’t cross inner mito mem (to leave mito)
so brought out as Citrate - citrate lyase cleaves it and regenerates acetyl CoA
malic enzyme
generates NADPH in cytosol
Malate -> Pyruvate
when can you afford to send citrate out of mito
good times!
acetyl CoA carboxylase
1
acetyl CoA +CO2 +ATP -> malonyl CoA (3Cs)
biotin is essential coenzyme (caroboxylases req it)
committed, rate-lim, regulated:
1. allosteric;
+citrate
-endprod-palmitic acid
- covalent: active deP (true of glycogen synthase too!), inactive if P; AMPK
- transcriptional reg, up-reg w high carb diet; via ChREBP at ChoRE
insulin also upregs
AMPK
AMP-activated protein kinase
rise in AMP:ATP ratio
major distress signal; hypoxia, exercise
AMP - most sensitive indicator of cell’s e state
P’lates acetyl CoA carboxylates = inhibits it
fatty acid synthase (FAS)
homodimeric, multifunctional (7 catalytic domain + aceyl carrier protein domain - the swinging arm)
Adds 2Cs from malonyl CoA to carboxylate end of an Acyl acceptor
How; rep seq of condense, reduce, dehydrate, reduce
NADPH used from PPP + malic enzyme
Primary Product; Palmite (16:0)
*shorter FA are possible - mothers milk
methylmalonyl CoA -> branched FA (plants)
can we make all the unsaturated fatty acids we need?
no. unable to insert a double bond after C10
can’t make n-6, or n-3
essential fatty acids; linoleic linolenic
FA; elongation paired with desaturation
palmitic acid - elongated to-> stearic acid - desaturated -> oleic acid
the essential fatty acids
linoleic
linolenic
used to make substrates for eicosanoid hormone synthesis
can’t insert C=C between C10 and omega C
fatty acid activation
fatty acyl-CoA synthetases
req ATP
focus; long chain FA
LCFA activation and transfer
activation in cytosol crosses the outer membrane Carmitine palmitoyl transferase 1 (CPT 1) removes the CoA -> Fatty acylcarnitine crosses the inner membrane Carnitine removed
Regulated, Rate limiting step
Malonyl CoA inhibits CAT-1 (synthesis of FA prevents FA oxidation)
SCFA MCFA are activated w/in the matrix
fatty acid oxidation
palmitine -> Acetyl CoA +7FADH2 +7NADH
Rep 4-step process:
- FAD-linked dehydrogenation
- hydration
- NAD-linked dehydrogenation
- thiolytic cleavage by CoA
Products: reducing equivalents & acetyl CoA
ETC -> ATP -> powers gluconeogenesis to feed the tissues that dont do FA ox
other things that get oxidized by CoQ (ubiquinone)
reducing equivalents from
fatty acid oxidation
glycerol 3 phosphate shuttle
dihydroorotate to OA (pyrimidine synthesis)
fatty acid beta oxidation, location, process
liver, muscle
beta-oxidation deals with FA that are…
even number of C
saturated
long chain
unbranched
dealing w odd # fatty acids
remove 2C at a time -> proprionyl CoA
proprionyl CoA carboxylase (biotin) -> methylmalonyl CoA
methlmalonyl CoA mutase (B12) ->succinyl CoA -> TCA -> glucose in liver
ONLY FA rxn that will synthesize Glucose
two B12 requiring rxns in the body
- methlymalonyl CoA -> succinyl CoA
methlmalonyl CoA mutase
to deal w odd numbered FA ox - remethylation of homocystinene -> homothionine
dealing w unsaturated FA
need to use additional enzymes bc the process generates an intermediate that cannot be used by the hydratase
VLCFA
in peroxisomes via ABC transporter (no carnitine)
have the synthetase to activated the VLCFA -> MCFA & acetyl CoA
link with carnitine and sent to mitochondria
Pathology; ABC transporter - childhood cerebral form X-ALD most severe phenotype, progresseive neurologic loss to veg state
dealing with branched chain fatty acid
derived from cholorophyll -> milk and meat
phytanic acid -> pristanic acid (not branched)
Defect= Refsum disease (phytanic acid storage disease) very rare
Zellweger syndrome
peroxisome biogenesis disorder
defect in proteins that recognize PTS
all functions of peroxisomal matrix proteins negatively affected
ZS most sever of a continuum, fatal by age 1 yr
ketogenesis
made in liver mitochondria
alternate fuel for brain
- 2C CoA +2C CoA = 4C CoA
- 4C CoA + 2C CoA = 6C CoA (HMG CoA)
- 6C CoA - 2C CoA = 4C (acetoacetate) by lyase
- 4C decarboxylated to 3C (acetone) + CO2
- 4C reduced to 4C (beta-hydroxybutyrate)
KB are actually 4C, water sol, organic acids
ketolysis
mitochondria of non-hepatic tissues
beta-hydroxybutyrate DH
acetoacetate: succinyl-CoA CoA transferase
thioase
why doesn’t ketolysis occur in the liver?
liver lacks transferase, so liver can make but not use KB
moves CoA onto acetoacetate
Fatty acids summary
structural components; triglycerides percursors; eiconsinoide hormones cytosolic synthesis; ACC,FAS mito beta-oxidation; CAT-1, e-rich citrate & carnitine to solve transport issues (in synthesis and oxidation) FA elongation & desaturation in ER limits to desturation; not past C10 => EssentialFA Peroxisomal oxidation of VLCFA
of Carbons;
MCFA
LCFA
VLACFA
MCFA - 6-12
LCFA - 14-20
VLACFA - >22
malate dehydrogenase rxn
OAA + NADH -> NAD+ + Malate
Biotin is a coenzyme for what enzyme in fatty acid synthesis? what vitamin is it from??
Acetyl CoA Carboxylase (ACC)
-among other carboxylases
B7
source of 2C units in fatty acid synethesis
malonyl CoA
primary FA produced
palmitic acid (16:0)
elongation of FA
occurs in ER (and mito)
more than one enzyme req - are ER memb proteins
CoA esters used
start w malonyl CoA
