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)
Coenzymes
Cosubstrates- 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
Coenzymes
• 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
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
Vitamin
Ascorbic acid (C)
Niacin
Riboflavin (B2)
Thiamin (B1)
Pyridoxal (B6)
Biotin
Folate
Cobalamin (B12)
Vitamin A
Vitamin K
Pantothenate (B3)
Vitamins
Coenzyme
not a coenzyme
NAD(P)+/NAD(P)H
FMN & FAD
Thiamin-pyrophosphate
Pyridoxal phosphate
Biotin
Tetrahydrafolate
adenosyl-and methylcobalamin
Retinal
Vitamin K
Coenzyme A
Niacin (nicotinic acid)
O
O
C
C
OH
N
NICOTINIC ACID
(NIACIN)
NH2
N
NICOTINAMIDE
• 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
NICOTINAMIDE MONOPHOSPHATE
Nicotinamide Coenzymes
H
O
O
C
C
NH2
C
OH
N
N
O
H2
C
NH2
N
NICOTINIC ACID
(NIACIN)
NICOTINAMIDE
O
PO2-
OH OH
NH2
O
H
ADENOSINE MONOPHOSPHATE
O
N
PO2-
N
O
N
OH OH(OPO3)
H
H
C
O
CH2
O
O
C
NH2
NH2
N
N
N
R
R
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 time
Quinone
form
Hydroquinone
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
OH
H2C
HC
O
HOH2C
N
NH3
O
H2C
O
HOH2C
N
CH3
H
O
HOH2C
N
CH3
H
PYRIDOXINE
H
PYRIDOXAL
PRYIDOXAMINE
NH3
O
HC
O
O
P
O
CH3
H2C
O
O
H2C
O
P
O
O
H2C
O
O
N
CH3
H
PYRIDOXAL 5' PHOSPHATE
N
CH3
H
PYRIDOXAMINE 5' PHOSPHATE
PYRIDOXAL-PHOSPHATE
•Important in amino acid metabolism
•Bound to enzyme as a Schiff base thru rxn with
lysine
O
- H2O
R
C
H
+
NH2
R
R2
+ H2O
ALDEHYDE
AMINE
C
H
N
R2
SCHIFF BASE
• PLP functions in transamination, decarboxylation,
racemization, isomerization, side-chain elimination
rxns involving amino acids
PLP in transamination
reaction
PLP in amino acid decarboxylation reaction