chemistry 7.1-cofactors-–-part-1
TRANSCRIPT
Chapter 7 (part 1)
Cofactors
Cofactors• Cofactors are organic or inorganic
molecules that are required for the activity of a certain conjugated enzymes
• Apoenzyme = enzyme (-) cofactor• Holoenzyme = enzyme (+) cofactor• Inorganic cofactors – essential ions• Organic cofactors – coenzymes
Essential Ion Cofactors• Activator ions – bind reversibly to enzyme
and often participate in substrate binding.• Metal ions of metalloenzymes – cations that
are tightly bound to enzyme and participate directly in catalysis (Fe, Zn, Cu, Co).
• Metal activated enzymes – require or are stimulated by addition of metal ions (i.e. Mg2+, is required by many ATP requiring enzymes)
Metal ions can function as electrophiles in
active site
Zinc protease (angiotensin converting enzyme)
CoenzymesCosubstrates-
- altered in rxn and regenerated to original structure in subsequent rxn- disassociated from active site- shuttle chemical groups among different enzyme rxns.
Prosthetic groups-- remains bound to enzyme- must return to original form
Both cosubstrates and prosthetic groups supply reactive groups not present on amino acid side chains
• Metabolite coenzymes – synthesized from common metabolites
• Nucleoside triphosphates – (ATP) can donate phosphates, pyrophosphates, adenosyl grroups
• S-adenosylmethionine (SAM) – donates methyl groups
• Nucleotide sugars (uridine diphosphate glucose = UDP-glucose) - transfer sugars in carbohydrate metabolism
Coenzymes
Vitamin derived coenzymes
• Must be obtained from diet• Synthesized by
microorganisms and plants• Vitamin deficiencies lead to
disease state• Most vitamins must be
enzymatically transformed to function as a coenzyme
VitaminsVitamin CoenzymeAscorbic acid (C) not a coenzymeNiacinNAD(P)+/NAD(P)HRiboflavin (B2) FMN & FADThiamin (B1) Thiamin-pyrophosphatePyridoxal (B6) Pyridoxal phosphateBiotin BiotinFolate TetrahydrafolateCobalamin (B12) adenosyl-and methylcobalaminVitamin A RetinalVitamin K Vitamin KPantothenate (B3) Coenzyme A
Niacin (nicotinic acid)
• Deficiencies lead to pellagra (dermatitis, diarrhea, dementia)
• Required in relatively high amounts compared to other vitamins
• Not true enzyme because can be synthesized from tryptophan in the liver
N
C
O
OH
N
C
O
NH2
NICOTINIC ACID(NIACIN)
NICOTINAMIDE
Nicotinamide Coenzymes
N
C
O
OH
N
C
O
NH2
NICOTINIC ACID(NIACIN)
NICOTINAMIDE
N
C
O
NH2
H
O
OHOH
H2C
O
PO2-
O
PO2-
O
O
OH(OPO3)OH
CH2 N
NN
N
NH2
NIC
OTI
NA
MID
E M
ON
OPH
OSP
HA
TEA
DEN
OSI
NE
MO
NO
PHO
SPH
ATE
N
C
O
NH2
H
R
N
C
O
NH2
H
R
H
OXIDIZED REDUCED
NAD+ / NADP+• Serve as cofactors in oxidation/reduction reactions• Act as co-substrates for dehydrogenases• Reduction of NAD+/NADP+ and oxidation of
NADH/NADPH occurs 2 e- at a time.• Function in hydride ion transfer• Rxns forming NADH/NADPH are catabolic• NADH is coupled with ATP production in mitochondria• NADPH is an impt reducing agent in biosynthetic
reactions• Reduced forms (NADH/NADPH) absorb light at 340 nm,
oxidized forms (NAD+/NADP+) do not
Riboflavin (B2)• Water soluble vitamin• Severe deficiencies lead to
growth retardation, reproductive problems and neural degeneration
• Meat, dairy products and dark green vegetables, legumes and grains are good sources
FMN/FAD
FAD and FMN can transfer electrons one or two at a
timeHydroquinone
formQuinone
form
semiquinone form
Thiamin
•Thiamin is the first Vitamin discovered (Vital amine = Vitamin)•Deficiencies lead to disease called Beriberi (neurological disorders, heart problems, anorexia)•Beriberi prevealent in undeveloped countries where polished grains make up the majority of the diet.•Associated with alcohol related disorders (Wernickes-Korskofff syndrome – memory loss, unstable walk)
Thiamin pyrophosphate
•Serves as a cofactor in decarboxylation rxn of keto acids •Also functions as a prosthetic group in transketolases (catalyze the transfer of two carbon units in carbohydrate metabolism)
Thiazolium ring is the chemically active part of
TPP
Ylid = a molecule with opposite charges on adjacent atoms
Pyridoxal
N
HOH2C
H2C
O
CH3
H
OH
N
HOH2C
HC
O
CH3
H
O
N
HOH2C
H2C
O
CH3
H
NH3
N
H2C
HC
O
CH3
H
O
OP
O
O
O
N
H2C
H2C
O
CH3
H
NH3
OP
O
O
O
PYRIDOXINE PYRIDOXAL PRYIDOXAMINE
PYRIDOXAL 5' PHOSPHATE PYRIDOXAMINE 5' PHOSPHATE
PYRIDOXAL-PHOSPHATE
CR
O
H + NH2 R2 R CH
N R2- H2O
+ H2OALDEHYDE AMINE SCHIFF BASE
•Important in amino acid metabolism•Bound to enzyme as a Schiff base thru rxn with lysine
• PLP functions in transamination, decarboxylation, racemization, isomerization, side-chain elimination rxns involving amino acids
PLP in transamination reaction
PLP in amino acid decarboxylation reaction