Lecture 41 Flashcards
Energy Metabolism II: TCA and ETC
1
Q
pyruvate dehydrogenase complex (PDH)
A
- converts pyruvate to acetyl CoA in the mitochondria; one of the carbons is removed and CoA carries the 2-C portion to donate it in metabolic pathways
- three separate enzymes that work at the same time (E1,E2,E3)
- five different coenzymes (all required for reaction to be efficient)
Coenzymes:
- thiamine pyrophosphate, TPP (from thiamine, vitamin B1)
- lipoamide (can be synthesized by human cells)
- coenzyme-A (CoA) (from pantothenic acid, vitamin B5)
- FAD (from riboflavin, vitamin B2)
- NAD+ (from nicotinamide, vitamin B3/niacin)
pg 1090
2
Q
PDH and human health: vitamin deficiencies
A
- deficiency of niacin or thiamine causes serious CNS problems
- Wernicke-Korsakoff syndrome (thiamine deficiency) -> often seen in chronic alcohol use disorder
- neurological symptoms occur from deficiency of any vitamins involved in metabolic processes
pg 1091
3
Q
PDH and human health: genetic defects in the PDH complex
A
Leigh Syndrome: subacute necrotizing encephalomyelopathy
- caused by mutation in either PDH, ETC protein or ATP-synthase
- rare, progressive neurodegenerative disorder
- chronic lactic acidosis
also, deficiency in the activity of the α-subunit of PDH (X-linked dominant)
pg 1091
4
Q
PDH and human health: arsenic poisoning
A
- arsenite forms a stable thiol with the -SH group in lipoic acid making it unavailable to serve as coenzyme
- affects the brain causing neurological disturbances and death
pg 1091
5
Q
PDH regulation
A
- complex multi-level regulation
- substrate activation (pyruvate, NAD+, CoA)
- product inhibition (acetryl CoA, NADH)
- covalent modifications: phosphorylation by a kinase deactivates PDH, dephosphorylation by a phosphatase activates PDH
- the PDH kinase and phosphatase can be allosterically regulated
Activators: pyruvate, NAD+, ADP, Ca2+, CoA
Inhibitors: acetyl CoA, NADH, ATP
kinase -> inhibitors: ADP, pyruvate; activators: acetyl CoA, NADH
phosphatase -> Ca2+ (released in muscle cells when contractions occur -> muscle needs energy so allows PDH to work)
pg 1092
6
Q
TCA (Krebs, Citric acid) Cycle: purpose
A
- TCA = tricarboxylic acid, Krebs = physician who discovered, citric acid = first intermediate produced
- the final pathway where the catabolism of carbohydrates, amino acids, and fatty acids converge and their carbon skeletons are converted to CO2 (and H2O is produced)
- terminal oxidation of all biomolecules -> energy is carried by NADH and FADH2 for the subsequent production of ATP in the ETC
- located in the mitochondrial matrix, in close proximity to the ETC
- amphibolic pathway -> provides substrates for gluconeogenesis and NEAA synthesis
pg 1094
7
Q
TCA (Krebs) Cycle: Key Steps (irreversible)
A
- citrate synthase (oxaloacetate + acetyl CoA -> citrate): produces the first intermediate, regulated by substrate activation and product inhibition
- isocitrate dehydrogenase (isocitrate -> α-ketoglutarate): rate-limiting step, regulated allosterically (inhibitors are ATP and NADH, activators are ADP and Ca2+ -> muscle contraction)
- α-ketoglutarate dehydrogenase complex (α-ketoglutarate -> succinyl CoA): similar to the PDH complex -> multiple copies of 3 enzymes with same coenzymes as PDH; inhibitors are its products (succinyl CoA) and activators are Ca2+ in muscle
pg 1095-1097
8
Q
step 6 of TCA cycle
A
- succinate dehydrogenase (embedded in inner mitochondrial membrane) always has tightly bound FADH
- FAD is similar to NAD+ (electron carrier) and highly reactive; hydrogen molecules bond are easily lost when exposed to water
pg 1097
9
Q
TCA Cycle summary of regulation
A
- low energy states activate
- low energy: high AMP/ADP, high NAD+
- high energy states inhibt
- high energy: high ATP, high NADH
pg 1098
10
Q
mitochondria: ETC function
A
- ETC couple the oxidation of the reduced carries produced by the TCA cycle with the production of ATP by oxidative phosphorylation
- components are embedded in the inner mitochondrial membrane (IMM)
- cristae in IMM increase SA to have a lot of proteins attached and produce ATP very quickly
pg 1099
11
Q
mitochondria: IMM composition
A
- cardiolipin is a unique lipid in mitochondria
- 2 molecules are esterified through their phosphate groups
- exclusive to the inner mitochondrial membrane
- maintains the structure and function of ETC complexes
pg 1100
12
Q
Barth syndrome
A
- TAZ gene mutations (~160) result in production of tafazzin proteins with little or no function
- linoleic acid not added to cardiolipin, which causes problems with normal mitchondrial shape and functions such as energy production and protein transport
- tissues with high energy demands are most susceptible
- WBCs have abnormally shaped mitochondria leading to a weakened immune system and recurrent infections
- very rare X-linked disease
pg 1100
13
Q
mitochondria number and oxidative capacity
A
- oxidative capacity is determined by number of mitochondria in the cell (more mitochondria, greater oxidative capacity)
- erythrocytes have no mitochondria (NO ATP through oxidative phosphorylation -> ONLY glycolysis.. 2 ATP per glucose)
- hepatocytes have very high mitochondrial content (liver is central organ for metabolism)
pg 1101
14
Q
Electron Transport Chain (ETC)
A
4 protein complexes split into oxidation-reduction components (accepts e- and donates to the next molecule) and mobile components
- oxidation-reduction components: flavin mononucleotide (FMN); Fe-S centers; iron (Fe) in cyt b, c1, c, a, and a3; copper (Cu) in cyt a and a3
- mobile components: coenzyme Q (CoQ) and cytochrome C (cyt c)
pg 1102
15
Q
structure of Fe centers: porphyrins
A
- porphyrins are cyclic compounds that readily bind metal ions, usually ferrous (Fe2+) or ferric (Fe3+) iron forming metalloporphyrin (a prosthetic group of some proteins); most common in humans is heme
Heme porphyrin
- structure: one Fe2+ coordinated in the center of the tetrapyrrole ring of protoporphyrin IX
- function: a prosthetic group for hemoglobin, myoglobin, the cytochromes in ETC, cytochrome p450 monooxygenase system (CYP), other enzymes (catalase, nitric oxide synthase, and peroxidase)
pg 1103
