lipid metabolism I Flashcards
major source of carbon for fatty acid synthesis is
dietary carbohydrates
fatty acid synthesis-overview
occurs primarily in ____
also occurs in ____ tissue, ____ , ____ and ____ ____ ____
requires coordination between ____ and ____ reactions
liver
adipose tissue, brain, kidneys, lactating mammary glands
cytosolic and mitochondrial
end product of FA synthesis
palmitic acid (16 carbon molecule)
precursor of FA synthesis
acetyl CoA (2 carbon molecule)
phase I of FA synthesis
cytosolic entry of Acetyl CoA (made in mitochondrial matrix but needed in cytoplasm)
phase II of FA synthesis
generation of Malonyl CoA (acetyl CoA is carboxylated to malonyl CoA. most important substrate in FA synthesis. RATE LIMITING REACTION)
phase III of FA synthesis
fatty acid chain formation (the enzyme Fatty Acid Synthase catalyzes 7 rxns that incorporate Acetyl CoA and Malonyl CoA into Palmitate, a C16 FA)
phase I - cytosolic entry of Acetyl CoA:
- condenstation of Acetyl CoA with ____ to form ____ (catalyzed by ____ ____ )
- transport of citrate from mitochondria to cytosol. via a ____ ____
- citrate converted back to ____ ____ and ____ (catalyzed by ____ ____ )
- oxaloacetate (OAA) reduced to ____ (catalyzed by ____ ____ )
regeneration of Oxaloacetate (OAA):
- malate transported into mitochondria via ____ ____ transporter and oxidized to ____ by ____ ____
- cytosolic malate converted to ____ by ____ enzyme. Pyruvate transported to mitochondira via pyruvate tranporter and carboxylated to OAA by pyruvate carboxylase
- oxaloacetate (OAA) citrate citrate synthase
- citrate transporter
- Acetyl CoA and OAA citrate lyase
- malate malate dehydrogenase
- malate-alpha ketoglutarate OAA malate dehydrogenase
- pyruvate malic
citrate lyase regulation:
activators:
inhibitors:
activators: glucose, insluin
inhibitors: PUFA, leptin
phase II Generation of Malonyl CoA:
- cytosolic Acetyl CoA (2 carbon) is converted to ____ ____ (3 carbon) by carboxylation.
- catalyzed by ____ ____ ____ (RATE LIMITING ENZYME OF FA BIOSYNTHESIS PATHWAY)
- ACC adds a ____ to acetyl CoA
- uses ATP (for energy) and ____ as co-factor
- ACC exists in dimeric ( ____ ) or polymeric ( ____ ) forms
- Malonyl CoA
- Acetyl CoA Carboxylase (ACC)
- CO2
- Biotin
- inactive active
regulation of Acetyl CoA carboxylase (ACC):
activators:
inhibitors:
activators: citrate, insulin
inhibitors: glucagon, epinephrine, high [AMP], palmitate, PUFA
malonyl CoA:
substrate for:
regulator - inhibits:
prevents FA synthesis and ____ from occuring simultaeneously
Fatty Acid Synthase (FAS)
carnitine acyltransferase (rate limiting step in FA degration)
degradation
phase III: FA chain formation:
- 2 carbon units from malonyl CoA are sequentially added to the growing fatty acyl chain in ____ rxns to form ____ (16:0)
- the rxns of FA synthesis occur on the ____ ____ ____ complex
- 7 rxns palmitate
- fatty acid synthase (FAS)
fatty acid synthase (FAS):
large ____-____ complex
composed of 2 identical ____
2 dimers arranged in ____ to ____ conformation
each monomer has ____ enzyme activites and an ____ ____ ____ (ACP)
multi-enzyme
dimers
head to tail
7 acyl carrier protein (ACP)
acyl carrier protein (ACP) has a ____ arm consisting of a ____ group that picks substrates and directs substrates to different enzymes in complex
flexible
phosphopantetheine
stoichiometry: palmitate synthesis reaction:
1 acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+ → CH3(CH214COO- (palmitate) + 14 NADP+ + 8 CoA + 6 H2O
reactions catalyzed by FAS
- first cycle
- Cys-SH of FAS binds to acetyl group
- Pan-SH on FAS binds to malonyl group
- condensation to form beta-ketoacyl group
- reduction
- dehydration
- reduction
- Cys-SH on FAS is now free
- 4-C fatty acyl group on Pan-SH is transferred to Cys-SH on FAS
- another new malonyl group is attached to Pan-SH and cycle repeats 6x
sources of NADPH
malic enzyme: 1 molecule of NADPH
pentose phosphate pathway: 2-12 molecules of NADPH
regulation of FA synthesis:
gene expression of the enzymes are induced by
low fat, high carb diet
(ATP citrate lyase) - phase I
(Acetyl CoA Carboxylase (ACC) - phase II - rate limiting step
(Fatty acid synthase) - phase III
regulation of ATP citrate lyase:
stimulated by ____
gene expression induced by ____/____
induction of gene expression counteracted by ____ ____ ____
induction of gene expression couteracted by ____
phosphorylation
glucose/insulin
polyunsaturated fatty acids (PUFAs)
leptin (hormone that senses fat content of body)
acetyl CoA carboxylase:
____ dimer , ____ polymer
inactive active
regulation of acetyl CoA Carboxylase:
- allosteric regulation
- activator:
- inhibitor:
- phosphorylation (inhibits) / dephosphorylation (activates)
- activators:
- inhibitors:
- induction
- gene expression up-regulated by ____ ____ / ____ ____ diet
- allosteric regulation
- activator: citrate
- inhibitor: long chain fatty acids (palmitate)
- phosphorylation (inhibits) / dephosphorylation (activates)
- activators: insulin via activation of protein phosphatase
- inhibitors:
- epinephrine via activation of PKA
- glucagon via activation of PKA
- AMP via activation of AMP kinase (energy sensory)
- induction
- gene expression up-regulated by high carb / low fat diet
regulation of Fatty Acid Synthase (FAS):
- allosteric effect (presence of phosphorylated sugars) - ____ activity
- induction and repression at gene level
- insulin and glucocorticoid hormones ____ synthesis
- high carb / low fat diet ____ synthesis
- high fat diets as well as starvation ____ synthesis
- high PUFA ____ synthesis
- increase
- increase
- increase
- lowers
- suppresses
synthesis of longer chain FA - elongation:
- elongation: palmitate converted to longer chain FA in ____ ____ ____ or ____
- brain cells need longer chain fatty acids ( ____ - ____ )
- FA lengthened 2 carbons at a time by the enzyme ____ ____ ____
- ____ is used as reducing power
- SER pathway uses ____ ____ as carbon donor
- mitochondria uses ____ ____ as carbon donor
- smooth endoplasmic reticulum (SER) or mitochondria
- C18 - C24
- Fatty Acid Elongase
- NADPH
- Malonyl CoA
- Acetyl CoA
desaturation (unsaturation) occurs in ____ ____ ____ , uses ____ and oxygen, and is catalyzed by ____ ____ ____
smooth ER NADPH (or NADH) Acyl CoA Desaturases
humans have ____ desaturases ( ____ , ____ , ____ , ____ )
4 delta4 , 5, 6, and 9
can introduce double bonds between carbons 4-5, 5-6, 6-7, and 9-10
FAs with double bonds beyond carbon 9 and 10 cannot
be synthesized in humans
e.g. omega 3 and omega 6 FA (need to ingest them or their precursors in diet)
precursors of FA with double bonds beyond carbons 9 and 10 are called
essential fatty acids
essential fatty acids:
need to ingest these via diet or their precursors:
linoleic acid (18:2 w6) and linolenic acid (18:3 w3)
linoleic acid used to make ____ acid (20:4 w6) a precursor for jeicosanoids (prostaglandins, leukotriences, and thromboxanes)
linolenic acid used to make ____ acid (EPA) (20:5 w3) and ____ acid (DHA) (22:6 w3)
arachidonic
eicosapentanoic docosahexanoic
*DHA is important for brain fxn; present in breast milk
benefits of w3 and w6 FAs
immune system
cardiovascular system
nervous system
vision
cell membrane
FAs are incorporated into
triacylglycerols (the storage form of lipids - used for energy)
pound for pound, TAGs contain about ____ times as much energy as ____
6.75
carbs
typical 70kg man fuel stores:
40 kCal ____ (blood)
600 kCal in ____ (liver and muscle)
24,000 kCal in ____ (muscle)
100,000 kCal in ____ (in fat and muscle)
glucose
glycogen
protein
TAGs
TAGs
backbone:
-OH are replaced with:
glycerol
fatty acids
building TAGs occurs in 3 locations:
dietary TAG (processed in ____ cells)
De Novo TAG (in ____ )
De Novo TAG (in ____ )
intestinal
hepatocytes
adipocytes
TAG synthesis in Liver:
glucose:
- glucose → ____ (via glycerol 3-phosphate dehydrogenase)
glycerol:
- glycerol → ____ (via glycerol kinase)
acetyl CoA:
- acetyl CoA → ____ ____ → ____ ____ ____ (via fatty acyl CoA Synthase)
overall:
- glycerol 3-P + fatty acyl CoA → ____ acid → ____ acid → diacylglycerol (DAG) → Triacylglycerol TAG → ____
glucose:
- glucose → glycerol 3-P (via glycerol 3-phosphate dehydrogenase)
glycerol:
- glycerol → glycerol 3-P (via glycerol kinase)
acetyl CoA:
- acetyl CoA → fatty acid → fatty acyl CoA (via fatty acyl CoA Synthase)
overall:
- glycerol 3-P + fatty acyl CoA → lysophosphatidic acid → phosphatidic acid → diacylglycerol (DAG) → Triacylglycerol TAG → VLDL
steps in TAG synthesis in liver
glycerol 3-P → lysophosphatidic acid → phosphatidic acid → diacyl glycerol → triacyl glycerol
TAG synthesis in liver key points:
- glucose and glycerol form ____ using different pathways
- Glucose 3-P used as ____ for TAG synthesis
- Free fatty acids (FFA) (synthesized in liver from ____ ____ ) added to glycerol 3-P to form TAGs
- TAGs packaged with apolipoproteins and other lipids (phospholipids) to form a lipoprotein called ____
- VLDL released into ____
- TAG synthesis in hepatocytes promoted by excess ____
- glycerol 3-P
- backbone
- acetyl CoA
- VLDL (very low density lipoproteins)
- bloodstream
- carbohydrates
TAG synthesis in adipocytes key points:
- glucose forms ____
- glycerol 3-P used as ____ for TAG synthesis
- Free fatty acids (FFA) (obtained from breakdown of ____ and ____ in blood) by the action of ____ ____ ____
- glycerol 3-P and free fatty acids form ____
- TAGs stored in ____
- TAG synthesis in adipocytes promoted by excess ____ and ____
- glycerol 3-P
- backbone
- chylomicrons and VLDL capillary lipoprotein lipase
- TAGs
- adipocytes
- carbohydrates and fats
