biochem_mod5_ms1

BMAX AND Ro= NUMBER OF AVAILABLE RECEPTORS = X-INTERCEPT

KD = AFFINITY; THE LOWER THE KD, THE HIGHER THE AFFINITY = -1/SLOPE

INITIATING SIGNAL - B-ADREN AMINES, GLUCAGON, PARATHYROID HORMONE, etc

DOWNSTREAM SIGNAL - ADENYLATE CYCLASE

INC cAMP --> STIM PROT KIN A

INITIATING SIGNAL - ACh, A-ADREN AMINE, NEUROTRANSMITTERS

DOWNSTREAM - PLC-B CLEAVES PIP2 INTO DAG & IP3 --> INTRACELLULAR Ca++

Ca++ & DAG STIM PKC

Ca++ STIMS CALMOD-DEPENDENT PROT KIN

INITIATING SIGNAL - ACh, A-ADREN AMINES, MANY NEUROTRANSMITTERS

DOWNSTREAM SIGNAL - INHIBITS ADENYLATE CYCLASE

1) INTRINSIC GTPase OF G-alpha SUBUNIT

2) DIS-ASSOCIATION OF LIGAND

3) PHOS OF RECEPTOR BY A RECEPTOR KINASE, CAUSING B-ARRESTIN TO BIND TO RECEPTOR AND PREVENT RECEPTOR FROM ACTIVATING G-PROT EVEN WHEN LIGAND IS BOUND (DESENSITIZATION)

CHOLERA - ADP-RIBOSYLATE Gs IN INTESTINE CAUSING LOSS OF GTPase ACTIVITY. ADEN CYCL ALWAYS ON AND cAMP ELEVATED

PERTUSSIS - ADP RIBOSYLATES Gi IN AIRWAY TISSUES CAUSING INABILITY TO EXCHANGE GTP/GDP. ADEN CYCL ALWAYS ON AND cAMP ELEVATED

1) RAS PATHWAY - EGF BINDS TO RECEPTOR AND INC TYROSINE PHOS --> RECRUITS MOLECULES CONTAINING SH2 DOMAINS (Grb-2) --> PROT ACTIVATIONS --> RAS --> MAP KINASE --> DNA SYNTH

2) PLC-gamma - ACTIVATION BY EGF RECEPTOR INC DAG, IP3, AND PKC. TUMOR PROMOTORS ACTIVATE PKC SIMILARLY TO EGF

3) PI3-K - CATALYSES ATTACHMENT OF PHOS GROUP TO 3 CARBON OF PIP2 (SAME PIP2 THAT BREAKS TO DAG AND IP3), PIP2 --> PIP3 --> ACTIVATES PROT KIN CASCADE THAT INCLUDES PDK1 AND PKB (Akt)

GROWTH AND METABOLISM

NON-INTRINSIC TYROSINE KINASE RECEPTORS

BUT, RECRUIT TK

BINDING TO RECEPTORS WITH GUANYLATE CYCLASE ACTIVITY

REGULATE Na AND BLOOD PRESSURE

cGMP --> PROT KIN G

NICOTINIC CHOLINERGIC RECEPTOR ON MOTOR END PLATE

FORM OF DOWN-REGULATION

METABOLIC STRESS CAUSES RELEASE OF GHRH: FASTING, HYPOGLYCEMIA, EXERCISE, SLEEP, AAs

IGF-1 REGULATES GROWTH AND METABOLISM, MEDIATES MANY OF THE GROWTH EFFECTS OF GH.

• GH:
• LIPOLYSIS
• PROT SYNTH
• BONE,MUSCLE,CART, SOFT TISSUEGROWTH
• GLUCONEOGENESIS
• INHIB MUSCLE GLUC UPTAKE

• IGF-1 (SIMILAR TO INSULIN EFFECTS)
• MUSCLE GLYCOLYSIS
• PROT SYNTH
• BONE,MUSCLE, etc

• GH
• RECEPTOR ACTIVATES TYROSINE KINASE JAK --> TPs TRANSCRIPTION FACTORS CALLED SIGNAL TRANSDUCERS & ACTIVATORS OF TRANSCRIPTION (STATs) --> BIND TO DNA PROMOTER/ENHANCERS ENCODING IGF-1. ALSO, INC FFA OX WILL ACTIVATE PYRUV CARB AND INH PYRUV DEHYD AND PFK-1 --> INH PFK-1 INCREASES GLUC-6-P --> INH HEXOKINASE --> INH GLYCOLYSIS & STIM GLUCONEOGEN

• IGF-1
• SIMILAR TO INSULIN RECEPTOR --> BIND a-SUBUNIT ACTIVATES TYROSINE KINASE OF b-SUBUNIT --> AUTOPHOS --> TYROSINE PHOS OF IRS & Shc --> BIND AND ACTIVATE PI3 KIN AND Grb-2 RESPECTIVELY --> MET & GROWTH CASCADE --> SKEL MUSCLE GLUC UPTAKE, INH OF GLUCONEOGEN IN KIDNEY.

LIVER & ADIPOSE HAVE VERY FEW IGF-1 RECEPTORS

GIGANTISM BEFORE PUBERTY & ACROMEGALY AFTER

• DUE TO:
• PITUITARY DAMAGE

MUTATION IN Gs CAUSING INC GH SYNTH & SECRETION --> DESTROY INTRINSIC GTPase ACTIVITY

GH RESISTANCE: LARON SYND. GH RECEPTOR MUTATION. POSSIBLE GIVE IGF-1

GH GENE DELETION

PITUITARY DAMAGE

MUTATIONS IN GH PRODUCTION & SECRETION: GHRH, GHRH RECEPTORS, TRANSCRIPTION FACTORS FOR GH GENE

IF SHORT STATURE BUT NO GH DEFICIENCY, DON'T GIVE GH

1) CATABOLIC ILLNESS/NEGATIVE NITROGEN BALANCE: GIVE BOTH GH AND IGF-1

2) ALS, MUSC DYST, SARCOPENIA (MUSC LOSS DUE TO AGING

3) TYPE II DIABETES: DON'T GIVE GH!

4) OSTEOPENIA, OSTEOPOROSIS, BONE FRACT REPAIR: IGF-1 MIGHT BE CRITICAL FOR PTH ACTION

5) INCLUDE IGF-1 BINDING PROTS WITH IGF-1 TO INC HALF-LIFE

GH RELEASED IN PULSATILE MANNER SO MEASURMENTS MAY BE INACCURATE: SERUM IGF-1 AND BINDING PROT BETTER INDICATOR

INTRAMUSCULAR IGF-1 INJECTION HARD TO DETECT

CANCER RISK IN PROSTATE, BREAST, & COLON

AMPHIPATHIC 27 CARBON STRUCT

A B C D RINGS

KEY REGULATOR OF MEMBRANE FLUIDITY: INC CHOL MAKES MEMs LESS FLUID AND INC Tm BY DISRUPTING INTERATIONS OF FATTY ACIDYL CHAINS AND COMPLEXING WITH PHOSPHOLIPIDS

SYNTHED MAINLY IN LIVER, INTESTINES, AND STEROIDOGENIC TISSUES

HMG-CoA REDUCTASE

1) NEGATIVE FEEDBACK BY HMG CoA REDUCTASE -- SYNTH CONTROLLED BY TRANSCRIPTION FACTOR SREB THAT BINDS TO DNA SEQUENCE SRE ON 5' SIDE. INACTIVATED BY ANCHORING TO ER OR NUC MEM. RELEASED BY PROTEOLYTIC CLEAVAGE WHEN CHOL LEVELS ARE LOW

2) RATE OF HMG CoA REDUCTASE TRANSLATION INHIBITED BY MEVALONATE METABOLITES AND DIETARY CHOL

3) DEGRADATION OF REDUCTASE: 2 DOMAINS. CYCLIC DOMAIN CATALYSES AND MAMBRANE SENSES DEGRADATION SIGNALS. INC STEROLS CAUSE CHANGE OLIGOMERIZATION STATE LEADING TO PROTEOLYSIS.

4) PHOS BY AMP-ACTIVATED PK DECREASES ACTIVITY OF REDUCTASE. CHOL SYNTH STOPS WHEN ATP IS LOW.

CHOL + 7a-HYDROXYLASE --> THC --> CHOLYL CoA (ACTIVE INTERMEDIATE) + GLYCINE OR TAURINE --> GLYCOCHOLATE (MAJOR) OR TAUROCHOLATE.

SERIES OF HYDROXYLATIONS BY P450

CHYLOs HAVE VLD AND ARE RELEASED FROM INTESTINES IN FORM OF LARGE LD CHYLOs

TAGs RELEASED BY LIPOPROTEIN LIPASES LINING BLOOD VESSLES AND TRANSPORTED BY ALBUMIN

LIVER TAKES UP CHOL RICH REMNANTS

EXCESS TAGs AND AND CHOL IN LIVER RELEASED AS VLDLs

BOTH VLDLs AND CHYLOs DEGRADED TO CHYLO REMNANTS

RESULTING REMNANTS FROM VLDLs ARE IDLs. HALF TAKEN UP BY LIVER AND HALF CONVERTED TO LDLs BY MORE TAG REMOVAL

RICHEST IN CHOL

MAJOR CARRIER OF CHOL

TRANSPORT CHOL TO PERIPHERAL TISSUES AND REG DE NOVO SYNTH

SHELL CONTAINS SINGLE PROT apo B-100 WHICH RECOGNIZES TARGET CELLS

AMOUNTS OF CHOL AND CHOL ESTERS IN LDLs ARE AROUND 2/3 OF TOTAL PLASMA CHOL

DIFFERENT FUNCTION

SHUTTLES CHOL THROUGHOUT BODY

PICKS UP UNESTERIFIED CHOL RELEASED FROM DYING CELLS (HDL₃ --> HLD₂)

EXCHANGES PROTS AND CHOL ESTERS WITH VLDLs AND CHYLOMICRONS

RENDERS CHOL MORE HYDROPHOBIC THUS EASIER TO TRANSPORT

LCAT IN PLASMA FOR HDLs

ACAT INTRACELLULAR TO MAKE VLDLs. HIGH UNESTERIFIED CHOL DISRUPTS CELL MEM INTEGRITY

MAJORITY OF BODY'S LDL RECEPTORS

MAJOR SITE OF CONVERSION OF CHOL TO BILE ACIDS

HIGHEST LEVEL OF HMG CoA REDUCTASE

1) APO-PROT B-100 ON LDLs BIND TO PROT CLATHRIN ON CELL PM (LOCATED IN COATED PITS)

2) RECEPTOR-LDL COMPLEX INTERNALIZED BY ENDOCYTOSIS. RECEPTOR THEN RECYCLED BACK TO MEM IN SEPARATE VESICLE

3) LDL VESICLE FUSES WITH LYSOSOME WITH VARIETY OF DEGRADING ENZYMES.

4) UNESTERIFIED CHOL USED FOR MEM BIOSYNTH, STORED USING ACAT, MADE INTO STEROIDS IN CERTAIN CELLS, OR RELEASED

1) INH HMG CoA REDUCTASE

2) ACTIVATES ACAT

3) LOWERS SYNTH OF LDL RECEPTORS (SREBP - SAME AS CHOL SYNTH CUZ BOTH HAVE SRE) -- EXCESS CHOL LEADS TO INC BLOOD CHOL [ ], WHICH ACCUMULATES

• LDL RECEPTOR HAS:
• EGF SIMILAR TO TRANSDUCIN b-SUBUNIT
• O-LINKED GLYCOSYLATION TO EXTEND RECEPTOR INTO LUMEN

LARGE PRECURSOR MOLECULE THAT CONTAINS:

ACTH --> INC cAMP --> PKA

MSH

CHOL RELEASE FROM CHOL ESTERS

CHOL TRANSPORT INTO MITOCHONDRIA

CHOL SIDE CHAIN CLEAVAGE --> PREGNENOLONE

GENERAL MUSCLE CATABOLISM

UNUSUAL REDISTRIBUTION OF FAT

GLUC INTOLERANCE

IMMUNE SUPPRESSION

ELECTROLYTE IMBALANCE, esp INC NA CAUSING HYPERTENSION

HYPERPIGMENTATION

• URINE CORT - 1000nmol NORM <250
• SERUM CORT - 500 / <50 AT MIDNIGHT
• SERUM ACTH - 100 / <80
• INABILITY TO SUPPRESS WITH DEXAMETHSONE

LIFE THREATENING

AUTOIMMUNE DESTRUCTION OF ADRENAL CELLS

IMPAIRED FORMATION OF ADRENALS

DEFICIENT ACTH RECEPTORS

IMPAIRED STEROIDOGENESIS: LOW CORT BUT HIGH ACTH (HYPERPIGMENTATION)

SECONDARY: LOW ACTH

HYPOGLYCEMIA, HYPOTENSION, DEHYDRATION, HIGH INFLAM RESPONSE

TREAT WITH CORT

HIGH CORT BUT NO EVIDENCE OF HYPERGLUCOCORT RESPONSE

MUTANT CORT RECEPTOR WITH <1000 FOLD AFFINITY

GR IN HYPOTHAL AND PIT ALSO MUTATED, CAUSING INC CRH --> ACTH --> CORT

RED - 17a-HYDROXYLASE

PURPLE - 17,20-DESMOLASE --> ANDROGENS

GREEN - 3b-DEHYDROGENASE

PINK - 21-HYDROXYLASE

BLUE - 11b-HYDROXYLASE (MITO)

LOW CORT, INC CRH ACTH AND DHEA

MALES --> PRECOCIOUS PUBERTY

FEM --> MASCULINE APPEARANCE & MALE EXTERNAL GENITALIA

LIFE-THREATENING DUE TO NA WASTING AND DEHYDRATION

LOW CORT, INC CRH ACTH MINERALCORTS (DEOXYCORTICOSTERONE) --> LOW RENIN HYPERTENSION

VARIABLE ALDOSTERONE LEVELS

MALES: NO ANDROGENS --> FEM APPEARENCE & EXT GENITALIA

FEM: NO ESTROGENS --> DEFECTIVE SECONDARY SEX CHARACTERISTICS AND NO MENSTRATION.

CAN RESULT IN BIPHASIC EFFECTS ON NA RETENTION: LOSS OF ALDOSTERONE --> NA WASTING AND DEHYDRATION EARLY IN LIFE

BUT WEAK MINERALOCORT DEOXYCORTICOSTERONE CAN CAUSE Na RETENTION LATER IN LIFE

aka VASOPRESSIN

INC BLOOD OSMOLALITY (NaCl [ ] DUE TO RETENTION OR WATER LOSS) BATH HYPOTHAL OSMORECEPTORS

RELEASED BY POST PIT

INC cAMP IN RENAL TUBULAR CELLS --> PKA --> AQUAPORIN-2 --> WATER REABSORPTION

ALSO INC SMOOTH MUSCLE CONTRACTION BY Gq --> INC CYTO Ca --> PKC & CALMOD ACTIVATED

• DISORDERS:
• DIABETES MELLITUS INSIPIDUS - TREAT W/ ADH

HEREDITARY NEPHROGENIC DIABETES INSIPIDUS: RARE - MUTATION IN ADH RECEPTOR

SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH): TUMOR PRODUCING ADH

REMOVAL OF 6-CARBON SIDE CHAIN FROM CHOL TO FORM PREG

CATALYZED BY CYTOCHROME P450 ENZYME CHOL DESMOLASE

STIMULATED BY ACTH

STEROID IN CIRCULATION DISSOCIATES FROM TRANSPORT PROT

DIFFUSE INTO CYTO OR NUC

BIND TO INACTIVATED RECEPTOR (INACTIVATED BY HEAT SHOCK PROTS)

TRANSLOC TO NUC

BIND TO HRE (HORM RESPONSE ELEMENT)

SYNTH OF NEW PROTS

DIFICIENT a5-REDUCTASE-2 --> DEC DHT

AUTOSOME RECESIVE MUT

PROMOTES DEV OF MALE EXTERNAL GENITALIA AND PROSTATE DURING EMBRYOGEN

DEFICIENT SYNTH OF CORT --> INC ACTH --> CONGENITAL ADRENAL HYPERPLASIA

INC DEOXYCORT --> INC MINERAL CORT --> LOW-RENIN HYPERTENSION

VARIABLE ALDOSTERONE

REDUCED ANDROGEN AND ESTROGEN

MOST COMMON CAUSE OF CONGENITAL ADRENAL HYPERPLASIA

IMPAIRED CORT SYNTH

INC ANDROGEN SYNTH --> PRECOSIOUS PUB (MALE) AND MALE GENITALIA (FEMALE)

CANNOT SYNTH BECAUSE OF LOCATION OF DOUBLE BONDS CLOSER THAN 7 Cs AWAY FROM o END

2 SEPARATE BIOSYNTH PATHWAYS FOR LENOLEIC AND LENOLENIC ACID

LINOLEIC ACID, o-6: MAINTAINS HEALTHY SKIN BY PREVENTING WATER LOSS. ACYLGLUCOSYLCERAMIDE (SPHINGOLIPID)

LENOLENIC ACID, o-3: --> 4,7,10,13,16,19-DOCOSAHEXAENOIC ACID IN RETINA.

o-3 THOUGHT TO ENHANCE CARDIO HEALTH BY REDUCING FAT PRODUCTION

DEC FAT SYTH BY INH FATTY ACID SYNTHASE AND HMG-CoA REDUCTASE

INC FATTY ACID DEGRADATION BY INC LIPOGENIC ENZYMES ACYL-CoA DEHYD AND CARNITINE PALMITOYLTRANSFERASE I.

NEURONS ACCUMULATE FOR MEM

LOCALLY ACTING HORMONES

MOSTLY DUE TO RAPID DEGRADATION

• 5 CATEGORIES TO KNOW:
• PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES, HETEs, AND PAF (NOT DERIVED FROM LENOLEIC)

LENOLEIC ACID --> ARACHIDONIC ACID --> CLEAVED BY PHOSLIPASE A2 FROM MEM --> COX ENZYME CONVERTS TO PROSTAGLANDIN PGG2 (COMMITED) --> PEROXIDASE CONVERTS TO PGH2

THROM INDUCES PLATELET AGG WHILE PROSTA DOES OPPOSITE

E INDUCES RELAXATION OF SMOOTH MUSCLE AND F DOES OPPOSITE

E ALSO INHIBITS GASTRIC ACID SECRETION, INFLAMMATION, FEVER, & PAIN

CONVERTS ARACHIDONIC ACID TO 5-HPETE

BIOSYTH OF HETEs AND LEUKOTRIENES

LEUKOs MADE MOSTLY IN LEUKOCYTES AND MAST CELLS -- INDUCE ASTHMA

PHOSPHOLIPASE A2 INH BY STEROIDS SUCH AS PREDNISONE AND DEXAMATHASONE. ADRENAL STEROIDS PROBALY DO SAME

ASPRIN INH COX (PROSTAs AND THROMBOs) BUT NOT LIPOXYGENASE (LEUKOs AND HETEs)

COX SELF-DESTRUCTS

ALL INACTIVATED METABOLICALLY -- VERY SHORT HALF-LIVES

1 - FOUND IN PLATELES, ENDO CELLS, KIDNEY, & LINING OF STOMACH. THROMBO SYNTH, PLATELET AGG, AND GASTRIC ACID SECRETION

2 - INFLAMMATION (LEUKOCYTES)

3 - ALT SPLICE OF COX 1, LARGELY IN BRAIN AND MEDIATES PAIN SENSATION

ASPRIN - INH ALL BUT PREFERS COX 1. ANTI-INFLAMM FROM INH COX 2 & SIDE EFFECTS FROM INH COX 1 (STOM ACID, ULCERS, BLEEDING)

COX 2 - CELEBREX, ROFECOXIB (VIOXX), MELOXICAM (MOBIC). INH INFLAMM WITHOUT COX 1 SIDE EFFECTS. ALSO INH CANCER DEV BY INDUCING APOP.

VIOXX PULLED - SO SPECIFIC TO COX 2 THAT INH PROSTACYCLIN PRODUCING CELLS IN HEART/AORTA/LARGE ARTERIES.

COX 3 - ACETAMINOPHEN (TYLENOL) DIMINISHES PAIN WITHOUT INH INFLAMM

o-6 FATTY ACIDS

ACTS ON CANNABINOID RECEPTOR

2-ARACH PRESENT IN BRAIN >170 ANANDA & HELPS PROTECT NEURONS DURING BRAIN INJURY BY INH INFLAMM

NOT ESSENTIAL FATTY ACID, BUT PHOSPHOLIPID & AUTACOID

CAUSES PLATELET AGG, EDEMA, HYPOTENSION, ALLERGIC INFLAMM, PSORIASIS, ITCHING, ASTHMA AND SHOCK

o-3: IMP FOR NUTRITION. WHEN INCLUDED IN MEMs TEND TO EXCLUDE CHOL

INH INFLAMM IN CHONDROs --> HELP ARTHRITIS

HIGH o-6 DIETS PRODUCE MORE PROSTAs, THROMBOs, AND LEUKOs THAN ANCESTORS --> INC BLOOD CLOTS, ASTHMA, ALLERGIES, HEART DISEASE, CANCER AND DIABETES. BUT GREATER RESISTANCE TO INFECTION

KNOW THIS

ESSENTIAL PROCESSES: ENZ ACTIVITY, HORMONAL RESPONSES, BLOOD COAGULATION, MUSCLE CONTRACTILITY & IRRITABILITY

FORMS: FREE, COMPLEXED (CHELATED) BY ORGANIC IONS LIKE CITRATE, AND PROT BOUND (45%) PRIMARILY ALBUMIN

LOW SERUM Ca STIMS FORMATION OF 1,25 DIHYDROXYD3 INC INTESTINAL ABSORPTION. VIT D NEEDED FOR Ca ABSORPTION

IF LOW Ca, 1,25(OH)2D3 AND PTH STIM BONE REABSORPTION

INTESTINES, BONE, KIDNEY

INTESTINES: ACTIVE VIT D 1a,25-(OH)2D3 INC BOTH Ca AND PHOSPHORUS

BONE: PTH INC BOTH, ACTIVE VIT D INC Ca, CALCITONIN (CT) DEC BOTH

KIDNEY: PTH INC Ca REABS AND DEC PHOS REABS, CT DEC BOTH, ACT VIT D INC Ca

PTC RELEASED BY CHEIF CELLS IN PT. RECEPTORS SENSITIVE TO SERUM Ca ACTIVATE G-PROT Gs WHEN Ca [ ] FALLS

ACTS ON INTESTINES, BONE, AND KIDNEY

ALSO A PROT RELATED HORMONE WITH SIMILAR ACTIONS (PTrH)

SERUM PHOS INC DEPRESSES SERUM Ca BY REDICING BONE RESORPTION AND DECREASING VIT D

PEPTIDE HORMONE RELEASED BY C CELLS IN THYROID GLAND

LOWERS SERUM Ca [ ] BY INH OSTEOCLASTS AND KIDNEY EXCRETION

HYPOCALCEMIA AND ACCOMPANYING HYPOPHOSPHATEMIA AFTER CT RELEASE

INC INTRACELLULAR Ca AND IP3 SUGGESTING PLC AND ADENYLYL CYCLASE