Chapter 16 Hemal Biochemistry The biochemistry and molecular biology department of CMU

Composition of the blood –The liquid element: plasma –The formed elements: red blood cells (erythrocytes), white blood cells (leukocytes), and platelets (thrombocytes). Plasma --- The blood fraction obtained after removal of the cellular components. Serum --- The liquid element obtained by allowing the blood to clot.

§1 Heme Synthesis

Sites: Mitochondria and cytoplasm Precursors: Glycine, succinyl CoA, Fe 2+

1. Synthetic pathway of heme (1) The formation of  -aminolevulinic acid (ALA) + HSCoA + CO 2 ALA synthase (pyridoxal phosphate) In the mitochondria

(2) The formation of porphobilinogen (PBG) ALA dehydratase 2H 2 O In the cytosol

(3) The formation of uroporphyrinogen Ⅲ (UPG Ⅲ ) and coproporphyrinogen Ⅲ (CPG Ⅲ ) 4× Porphobilinogen Linear tetrapyrrol UPG Ⅲ CPG Ⅲ Deaminase UPG Ⅲ isomerase UPG Ⅲ decarboxylase In the cytosol

Protoporphyrinogen Ⅸ Protoporphyrin Ⅸ Heme ferrochelatase (4) The formation of heme CPG Ⅲ oxidase CPG Ⅲ Protopor- phyrinogen Ⅸ oxidase In the mitochondria

Heme Protoporphyrin Ⅸ Protoporphyrinogen Ⅸ CPG Ⅲ UPG Ⅲ Linear tetrapyrrol PBG Gly succinyl CoA

(1) ALA synthase Rate-limiting enzyme Feedback-inhibition by heme Intensity inhibition by Ferriheme Inducing by some drugs and hormones (eg. testosterone) 2. Regulation of heme biosynthesis

(3) Erythropoietin (EPO) can increase synthesis of heme and hemoglobins. (2) ALA dehydrase and ferrochelatase Inhibited by heme, and heavy metals.

§2 Metabolism of Bile Pigment and Jaundice

bile pigment is the main catabolic product of iron porphyrin compound in the body, consisting of bilirubin, biliverdin, bilinogen and bilin.

＊ The source of bilirubin The compounds involving iron prophyrin in the body are hemoglobin, myoglobin, cytochrome, peroxidase, and catalase, etc. 1. Formation and transport of bilirubin

＊ Formation of bilirubin site In the microsome and cytosol of monokaryon- macrophage system of the liver, spleen, and bone marrow.

process

The spatal structure of bilirubin property hydrophobic

＊ Transport of Bilirubin Form of Transport Bilirubin-albumin complex

2. Bilirubin conversion in liver ＊ Uptake ＊ Transport Smooth Endoplasmic reticulum Combine with ligandin

＊ Conjugation Bilirubin monoglucuronide bilirubin UDP UDP- glucuronyl transferase UDPGA Bilirubin diglucuronide UDPGA UDP UDP- glucuronyl transferase

structure of bilirubin diglucuronide

＊ Excretion Conjugated bilirubin is secreted into the bile and then excreted into the intestine.

Conjugated bilirubin bilinogen coliform Glucuronic acid Bilin oxidized ＊ process 3. Metabolism bilirubin in the intestine Free bilirubin reduced

Bilinogen enterohepatic circulation In the terminal ileum and large intestine, a small fraction of the urobilinogens is reabsorbed and reexcreted through the liver to constitute the enterohepatic cycle of urobilinogen.

4. Serum bilirubin and jaundice Conjugated bilirubin is also called direct reacting bilirubin or hepatobilirubin. ＊ Serum bilirubin 1 ～ 16  mol/l (0.1 ～ 1mg/dl) Free bilirubin is also called indirect reacting bilirubin or hemobilirubin.

free bilirubin conjugated bilirubin Binding with Glucuronic acid no yes Reacting with the diazo reagent Slow and indirect Rapid and direct solubility in watersmalllarge Discharged via kidneynoyes Pass through the membrane of cell yesno difference of two bilirubins

Jaundice Hemolytic (prehepatic) jaundice Hepatocellular (hepatic) jaundice Obstructive (posthepatic) jaundice

Laboratory results in patients with jaundice normal Hemolytic jaundice Hepatocellular jaundice Obstructive jaundice Serum bilirubin total < 1mg/dl > 1 > 1 > 1 direct 0~ 0.8mg/dl ↑ indirect < 1 Urine bile pigments urobilirubin ––+ urobilinogenA few ↑ uncertainty ↓ urobilinA few ↑ uncertainty ↓ Color of fecesnormaldark Simple or normal Clay color ↑ ↑ ↑