Bilirubin

Volume I: Chemistry

Karel P. M. Heirwegh

• Publisher: CRC Press
• Year: 2018
• Print ISBN:
  9781315891002
• eBook ISBN:
  9781351087001
• Topic: Medicine
• Subtopic: Alternative & Complementary Medicine

The book appears in two volumes, the first dealing primarily with chemical and structural aspects, and the second with metabolic aspects. The purpose is not only to review recent work on chemical and physiological aspects of bilirubin scructure and metabolism, but also to emphasize the importance of methodological advances and their potential in future studies.

Chapter 1

STRUCTURE, PHOTOCHEMISTRY, AND ORGANIC CHEMISTRY OF BILIRUBIN*

David A. Lightner

TABLE OF CONTENTS

I. Nomenclature

A. Bilirubin and Its Conjugates

B. Dipyrrole Azo Derivatives from Bilirubin

II. Structure

A. Primary Structure

1. Degradation

a. Resorcinol Melt

b. Oxidation

c. Diazo Cleavage

2. Total Synthesis

B. Secondary Structure

1. Lactam-Lactim Tautomerism

a. X-ray Crystallography

b. Infrared Spectroscopy

c. Nuclear Magnetic Resonance (NMR) Spectroscopy

2. Z/E Configurational Isomerism

C. Tertiary Structure

D. Aggregation

III. Photochemistry

A. Electronic Excited States

B. Reactions of Excited States

1. Geometric Configurational Isomerism

2. Constitutional Isomerism

3. Photoaddition to Vinyl Groups

4. Photooxidation and Singlet Oxygen

5. Other Photochemical Reactions

C. Phototherapy

IV. Synthetic Procedures

A. From Heme and Verdins

B. Partial Synthesis by Left Half-Right Half Scrambling

C. Total Synthesis

D. Labeled Biladienes

References

I. NOMENCLATURE

A. Bilirubin and Its Conjugates

Attempts have been made to produce a useful, systematic naming system for tetrapyrroles. The IUPAC-IUB Joint Commission on Biochemical Nomenclature has proposed² that linear tetrapyrrole names should be based on a fundamental carbon/nitrogen skeletal structure called “bilin” as illustrated in Figure 1. Chemical Abstracts currently uses a variation of this nomenclature with a root name 21 H-biline as opposed to bilin in the 22H-form. In either case, it should be noted that position 20 does not appear; it corresponds to the extra main atom, e.g., carbon, that would be required to transform the linear tetrapyrrole into a macrocyclic porphyrin structure. Fortunately, bilirubin-IXα is allowed to retain the common name “bilirubin” (here meaning specifically the IXα structure),² although Chemical Abstracts currently indexes it under the cumbersome systematic name: 2,17-diethenyl-l, 10, 19, 22, 23, 24-hexahydro-3, 7, 13, 18-tetramethyl-1, 19-dioxo-21 H-biline-8, 12-dipropanoic acid. (Note that in the latter name, vinyl is given priority over methyl, thus bilirubin is 2, 17-diethenyl and not 3, 18-diethenyl.) The IUPAC-IUB proposal² leaves the less natural bilirubins, e.g., bilirubin-IIIα or bilirubin-IXβ, to be named systematically. In view of their simplicity, common names will no doubt continue to be preferred in many instances.

Further designations are required in order to specify stereochemical features of the molecules. In particular, one should note that geometric configurational isomers exist at the carbon-carbon double bonds located between atoms 4 and 5,10 and 11, and 15 and 16. To distinguish between the two possible geometric isomers at each carbon-carbon double bond, the standard notations Z (zusammen) and E (entgegen)³ are used. In this nomenclature, priorities are assigned to each atom (or group) attached to each carbon atom of the carbon-carbon double bond: at position 4, N(21) is higher priority than C(3) because N has a larger atomic number than C; at position 5, C(6) is higher priority than H because C has a larger atomic number than H. When the higher priority atoms (groups) are on the same side of the carbon-carbon double bond, the configuration is Z; when they are on opposite sides, the configuration is E. The stereochemical designations are illustrated in Figure 2 with the four possible different geometric isomers of bilirubin.

Additional recognizable stereochemical features may be found through rotations about the carbon-carbon single bonds between 5 and 6, 9 and 10, and 14 and 15. When imposed on the configurational isomers recognized and designated as above, two more forms obtain for each Z and E isomer. This is true because focal points, viz., the N atoms, may appear near (syn) or away (anti) from each other in the planar projections.⁴ This is illustrated in Figure 3.

Another nomenclature which is specifically directed toward bilirubin and biliverdin structures has been submitted to the IUPAC-IUB Joint Commission on Biochemical Nomenclature and is acceptable to Chemical Abstracts.⁵ The retention of the core names bilirubin (for bilirubin-IXα) and biliverdin (for biliverdin-IXα) is proposed. For other isomers of bilirubin or biliverdin, the core names are used in conjunction with designations for the locations of vinyl and propionic acid groups, as illustrated in Figure 4. This nomenclature allows for easy designation of conjugates, e.g., bilirubin glucuronides, according to the tetrapyrrole structure and the sugar derivatives that are shown in Figure 5. In most instances the sugar is in the pyranose form and is attached through the β-linkage at the anomeric carbon (C-1’). It is proposed that the mode of linkage not be specified unless it is different from ß, and that the pyranose symbol (p) be deleted in the abbreviation because the sugars have not been observed to occur naturally in a different form. Thus ordinary bilirubin-IXα diglucuronide would become named bilirubin-8,12(GlcU; GlcU). The nomenclature differentiates between the two possible position isomers of bilirubin monoglucuronide by italicizing or underlining the number of the propionic acid side chain to which the sugar is attached. When the isomeric position is unknown, the number is not italicized or underlined. If two different sugars are attached, that, too, may be indicated in the bracketed part of the name. Synthetic esters can also be named in this system: bilirubin dimethyl ester becomes bilirubin-8,12(Me; Me). Examples of applications of the nomenclature may be found in Figure 6 and Table 1, and more varied examples are shown in Reference 5.

FIGURE 1. (Upper) Proposed systematic nomenclature for linear tetrapyrroles.² (Middle) Chemical Abstracts nomenclature. (Lower) Bilirubin-lXα has the systematic names: I,l0,l9,21,23,24-hexahydro-2,7,13,17-tetramethyl-l, 19-dioxo-3,18-divinylbilin-8,12-dipropanoic acid², or 8, 12-bis(2-carboxyethyl)-l0, 21, 23, 24-tetrahydr o-2,7,13,17-tetramethyl-3,18-divinyl-bilin-l,19-dione (Ref. 2 proposed) or 8,1...

Table of contents

• Cover
• Title Page
• Copyright Page
• Preface
• The Editors
• Contributor
• Acknowledgments
• Bilirubin
• Table of Contents
• 1. Structure, Photochemistry, and Organic Chemistry of Bilirubin
• 2. Bilirubin Conjugates: Isolation, Structure Analysis and Synthesis
• 3. Physical Chemistry of Bilirubin: Binding to Macromolecules and Membranes
• 4. Analytical Chemistry of Rubins
• Index