BlockII

!"##$%&' )*+,"-. /,"0&*'

!"#$ &'((")*# +,-*"-*-. -&/01$2 1,3"!,# 4 +*5,&,*#&$

ENZYMES
Protein catalysts
increase reaction rates, not consumed

ENZYMESUBSTRATE (ES) COMPLEX
E + S -> ES -> EP -> E + P
Cofactors) metal ion small organic molecules
Cosubstrates, transiently associate, Derived from VITAMINS
NAD+ (B3) coenzyme A (B5) FAD (B2)
ENZYMES (pathways) ARE SEGREGATED


REACTI0N



TRANSITION-STATE STABILIZATION


iate vs substiate concentiation


Vmax at high substrate concentrations = Substrate Saturation
&'123& ,&%-#$0*"' responses to changes in substrate
concentration, temperature, and pH


What Amino Aciu the enzyme is titiating at each pB.

MICHAELIS-MENTEN KINETICS


Km = affinity of the enzyme foi that substiate.
vmax is max speeu of the ieaction


Consiuei effect of inhibitois of enzyme action (BR0uS)
#45676896:;+<:= >?@A (uouble-iecipiocal plot)




STATIN DRUGS antihyperlipidemic



!-lactam antibiotics (penicillin and amoxicillin) Angiotensin-
converting enzyme (ACE) inhibitors
ALLOSTERIC ENZYMES
Usually multiple subunit proteins
Allosteric effectors that bind noncovalently (recall Hb)


Homotropic effectors
Heterotropic effectors
REGULATION BY COVALENT MODIFICATION Kinase (ATP
as donor) and phosphatase



Enzymes in Clinical Diagnosis
6?698A6B >?8CD8 65EFD6 levels plasma may inuicate tissue uamage
enzyme levels aie uiagnostic of uiseases of the G68:AH ?496:H C=6?6A8?
D<CI?6

alanine aminotiansfeiase (ALT) livei
elevateu levels of !"# in plasma possible uamage to hepatic tissue

*C@65EFD6C 85B B4C68C6C @J AG6 G68:A
%&'()*+' ,*+(-' (CK) S isozymes
CK1, CK2, CKS
CK2 heait muscle maikei

45J8:IA4@5
CK2 onset in plasma 4 to 8 his
CK2 peak ~ 24 houis
CK2 baseline 48-72his

Caiuiac tioponin I (cTnI)

45J8:IA4@5
cTnI onset in plasma 4 to 6 houis
cTnI peak ~ K A@ LK G@<:C
cTnI baseline M A@ NO B8FC












*'.-#*' $'P %#-!$%"'

LIvER, ABIP0SE, N0SCLE, ANB BRAIN

Neuiateu by
56:9@<C system,
ciiculating C<QCA:8A6C
levels of plasma G@:D@56C

two peptide hormones: INSULIN and GLUCAGon

CATECHOLAMINES
epinephrine and norepinephrine (survival crises, such as famine, severe injury,
and fight-or-flight) B@>8D456H 6>456>G:456;8B:658?456



*'.-#*'
$'$+"#*!
synthesis of glycogen, tiiacylglyceiols, anu piotein
polypeptiue hoimone (glycosylateu)
cells, islets of Langeihans


Inactive piecuisois, >:6>:@45C<?45 anu >:@45C<?45



C6I:6A@:F R:85<?6C
Releaseu by 6S@IFA@C4C
Balf-life *+ .*./ ~ 6 minutes INS0LINASE in bloou plasma


*5C<?45 C6I:6A4@5 iecipiocally cooiuinateu with R?<I8R@5 C6I:6A4@5
Insulin synthesis anu secietion aie 45I:68C6B by

+?@@B %#-!".& TD@CA 4D>@:A85AU
B cells have ulut-2 anu glucokinase
$D45@ $I4BC
Plasma Aiginine
%8CA:@45A6CA458? G@:D@56C
oial glucose (anticipatoiy insulin inciease)
peptiues small intestine (incietins)


*'.-#*' P&!,&$.&
Scaicity of uietaiy fuels
Stiess (fevei oi infection)
&/*'&/V,*'& T&"3*&6'(8D456H B@>8D456H 6>456>G:456;8B:658?456U
auienal meuulla (stiess, tiauma, extieme exeicise)
"W&,,*P& AG6 5@:D8? R?<I@C6;CA4D<?8A6B :6?68C6 @J 45C<?45
&>456>G:456 Q45BC !;8B:656:R4I :6I6>A@:C T%/!,U @5 +;I6??C ;X YI$3/


Note: pool of ieceptois in muscle anu auipose is uL0T-4
Bepatocytes, eiythiocytes, neivous system, intestinal mucosa, ienal tubules, anu
coinea use uL0T-2, insulin inuepenuent glucose absoiptioin





,&!&/0", 02,".*'& Z*'$.& !$.!$P&


PKC activates gene expiession
uL0C0KINASE, PB0SPB0FR0CT0KINASE, ANB PYR0vATE KINASE

*'.-#*' ,&./"'.& "))
C-Cbl piotein binus Ract
ubiquitinate

iemains as stoiage vesicle foi IR

Insulin uegiaueu in the lysosomes

*'.-#*' *'!,&$.& <>;:6R<?8A6C
ulucose uptake (most cells)
ulycogen synthesis
Piotein synthesis
Fat synthesis
Auipocytes
Inhibit (uephosphoiylate) Boimone sensitive lipase -> ueciease
tiiacylglyceiol uegiauation

*'.-#*' P&!,&$.&
uluconeogenesis
ulycogenolysis
Lipolysis
Auipocytes
Becieaseu tiiacylglyceiol uegiauation
Incieaseu tiiacylglyceiol synthesis


%#-!$%"'H 6>456>G:456H I@:A4C@?H 85B R:@7AG G@:D@56
[I@<5A6:;:6R<?8A@:F G@:D@56C\





%#-!$%"'
u cells of the pancieatic islets of Langeihans
conveiteu to glucagon thiough a seiies of selective pioteolytic cleavages,
piepioglucagon is piocesseu to uiffeient piouucts in uiffeient tissues.



.0*3-#$0*"' ") .&!,&0*"'
Low bloou glucose
Coiiect oveinight oi fasting hypoglycemia
Amino acius
Piotein meal stimulates both insulin anu glucagon

Epinephiine (auienal meuulla)
sympathetic inneivation of pancieas
oveiiiues insulin

%?<I8R@5 C6I:6A4@5 45G4Q4A4@5
Elevateu bloou glucose anu insulin.
Well feu state: ingestion of glucose oi a caibohyuiate-iich meal

NETAB0LIC AFFECT
!8:Q@GFB:8A6
Inciease Bloou ulucose
#4>4B
Activate lipolysis in auipose
-> acetyl-CoA -> Ketone bouy synthesis


/:@A645
Incieaseu uptake of amino acius by the livei -> caibon skeletons foi
gluconeogenesis
Plasma levels of amino acius aie uecieaseu

V2/"%#2!&3*$
1 cential neivous system (CNS) symptoms
confusion, abeiiant behavioi, oi coma
2 bloou glucose level equal to oi less than 4u mgul
S symptoms iesolveu within minutes following the auministiation of glucose

CNS ceiebial uysfunction piolongeu hypoglycemia = B68AG

V2/"%#2!&3*$
! inc glucagon, epinephiine, ueciease insulin

$B:656:R4I CFD>A@DCanxiety, palpitation, tiemoi, anu sweating
Epinephiine ielease by hypothalamus
Abiupt glucose ueciease
'6<:@R?FI@>6548the impaiieu ueliveiy of glucose to the biain


HYPOGLYCEMIC GLUCOREGULATORY SYSTEMS

islets of Langerhans, which release glucagon

receptors in the hypothalamus (sense low glucose)
counter regulatory hormone release
secretion epinephrine (inhibit insulin release)
late stage Type 1 diabetes
release of adrenocorticotropic hormone (ACTH) and growth hormone by
the anterior pituitary

HYPOGLYCEMIA TYPES
Insulin-induced hypoglycemia
Mild treat with oral carbohydrates
Severe (unconscious) subcutaneous/intramuscular glucagon

Reversal of insulin-induced hypoglycemia by administration of subcutaneous
glucagon

Postprandial hypoglycemia
exaggerated insulin release following a meal, prompting transient
hypoglycemia with mild adrenergic symptoms
eat frequent small meals

Fasting hypoglycemia
Rare
Serious medical problem
Neuroglycopenia symptoms,
reduction in the rate of glucose production by the
hepatocellular damage or adrenal insufficiency
fasting individuals who have consumed large quantities of ethanol
elevated insulin resulting from a pancreatic !-cell tumor

IF UNTREATED, CONVULSIONS AND COMA

Alcohol (Ethanol) Metabolism

Ethanol -----------------------" Acetaldehyde -----------------------" Acetate
Alcohol DH Aldehyde DH
NADH NADH



NADH favors pyruvate --" lactate and oxaloacetate -" malate
Pyruvate and oxaloacetate are Intermediates of gluconeogenesis
Alcohol inhibits gluconeogenesis -> hypoglycemia

PATIENT USING INSULIN RISKS ALCOHOL INDUCED HYPOGLYCEMIA
WITH A DELAY OF HOURS




The integration of energy metabolism is controlled primarily by insulin and the
opposing actions of glucagon and epinephrine (Figure 23.16). Changes in the
circulating levels of these hormones allow the body to store energy when food is
available in abundance, or to make stored energy available, for example, during
survival crises, such as famine, severe injury, and fight-or-flight situations.
Insulin is a polypeptide hormone produced by the ! cells of the islets of
Langerhans of the pancreas. The biosynthesis involves two inactive precursors,
preproinsulin and proinsulin, which are sequentially cleaved to form the active
hormone. A rise in blood glucose is the most important signal for increased
insulin secretion. The synthesis and release of insulin are decreased by
epinephrine, which is secreted in response to stress, trauma, or extreme
exercise. Insulin increases glucose uptake (by muscle and adipose) and the
synthesis of glycogen, protein, and triacylglycerol. These actions are mediated by
the binding of insulin to the insulin receptor, which initiates a cascade of cell-
signaling responses, including phosphorylation of a family of proteins called
insulin receptor substrate (IRS) proteins. Glucagon is a polypeptide hormone
secreted by the " cells of the pancreatic islets. Glucagon, along with epinephrine,
cortisol, and growth hormone (the counter-regulatory hormones), opposes
many of the actions of insulin. Glucagon acts to maintain blood glucose during
periods of potential hypoglycemia. Glucagon increases glycogenolysis,
gluconeogenesis, lipolysis, ketogenesis, and uptake of amino acids. Glucagon
secretion is stimulated by low blood glucose, amino acids, and epinephrine. Its
secretion is inhibited by elevated blood glucose and by insulin. Glucagon binds to
high-affinity receptors of hepatocytes. This binding results in the activation of
adenylate cyclase, which produces the second messenger, cyclic AMP (cAMP).
Subsequent activation of cAMP-dependent protein kinase results in the
phosphorylation-mediated activation or inhibition of key regulatory enzymes
involved in carbohydrate and lipid metabolism. Hypoglycemia is characterized by:
1) central nervous system symptoms, including confusion, aberrant behavior, or
coma; 2) a simultaneous blood glucose level equal to or less than 40 mg/dl; and
3) resolution of these symptoms within minutes following the administration of
glucose. Hypoglycemia most commonly occurs in patients receiving insulin
treatment with tight control. The consumption and subsequent metabolism of
ethanol inhibits gluconeogenesis, leading to hypoglycemia in individuals with
depleted stores of liver glycogen. Alcohol consumption can also increase the risk
for hypoglycemia in patients using insulin.